# ent

id: cord-006082-x1kankxd
type: GGP
entity:
  Rev Endocrinol DOI 10 1038 nrendo 2015 6 sha 3daed4a814faa5983f3582e85905d19ae0bb1a0d doc_id 6082 cord_uid x1kankxd The renin angiotensin aldosterone


id: cord-006082-x1kankxd
type: GGP
entity:
  mineralocorticoid receptor Abbreviations ACE angiotensin converting enzyme ACE2 angiotensin converting enzyme 2 Ang angiotensin ARB angiotensin receptor blocker ARN angiotensin receptor neprilysin AT1 type 1 Ang II receptor AT2 type 2 Ang II receptor IRAP leucyl cystinyl aminopeptidase


id: cord-006082-x1kankxd
type: GGP
entity:
  AT1 type 1 angiotensin II receptor AT2 type 2 angiotensin II receptor IRAP leucyl cystinyl aminopeptidase


id: cord-006082-x1kankxd
type: GGP
entity:
  ACE angiotensin converting enzyme ACE2 angiotensin converting enzyme 2 Ang angiotensin ARB angiotensin receptor blocker


id: cord-006082-x1kankxd
type: GGP
entity:
  angiotensin receptorneprilysin AT1 type 1 angiotensin II receptor AT2 type 2 angiotensin II receptor IRAP leucyl cystinyl aminopeptidase


id: cord-001961-0ic7twhy
type: PROTEIN
entity:
  angiotensin converting enzyme 2 angiotensin 1 7 Mas axis Angiotensin converting enzyme 2 angiotensin 1 7


id: cord-001961-0ic7twhy
type: GO
entity:
  basement membrane arteriolar hyalinosis and tubulointerstitial fibrosis 17 An ideal model of DN would


id: cord-002307-gk84fnb9
type: GGP
entity:
  insoluble amyloid β Aβ load r 0 199 P 0 059 and p tau load r 0 252 P 0 05 e Bar chart showing a trend towards increased ACE 1 ACE 2


id: cord-002307-gk84fnb9
type: GGP
entity:
  Alzheimer s disease vascular dementia and other dementias Prevention of dementia in randomised double blind placebo controlled Systolic Hypertension


id: cord-002307-gk84fnb9
type: CHEMICAL
entity:
  ACE 1 4 We speculate that the sequential cleavage of Aβ 43 first by ACE 2 and the subsequent cleavage of Aβ 42 to Aβ 40 the


id: cord-000570-0qkzd2w4
type: CHEMICAL
entity:
  angiotensin 1 7 in the regulation of matrix metalloproteinases of human cardiocytes Angiotensin 1 7 ameliorates myocardial remodeling and


id: cord-016335-z2movens
type: PROTEIN
entity:
  Angiotensin Converting Enzyme 2 date 2010 06 15 journal Hypertension and Hormone Mechanisms DOI 10 1007 978 1 59259 987 5_3 sha ba16ab17af96d56baf772b1e64f102550dff4511 doc_id 16335 cord_uid z2movens


id: cord-274259-voyzq05n
type: CHEMICAL
entity:
  angiotensin 1 7 on cell volume regulation Angiotensin 1 7 reduces the cell volume of swollen cardiac cells and decreases the swelling dependent chloride


id: cord-006439-q7m4srvp
type: DNA
entity:
  bacterial artificial chromosome transgenic AT 2 R enhanced green fluorescent protein eGFP reporter mouse


id: cord-006439-q7m4srvp
type: WORK_OF_ART
entity:
  The Renin Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation date 2020 01 10


id: cord-006302-pnnkfid0
type: ORG
entity:
  the Ethics Committees of Korinthos General Hospital Korgialeneion Benakeion General Hospital ATTIKON University Hospital


id: cord-287207-z6ddajd6
type: PROTEIN
entity:
  Renin Angiotensin System RAS DOI 10 1016 b978 0 12 801364 9 00038 9 sha dc99f561c0577db6ff057c19347a9bf9f1c09456 doc_id 287207 cord_uid z6ddajd6 Experimental


id: cord-015859-5kt59ose
type: PROTEIN
entity:
  phospholipase A 2 arachidonic acid pathway the phospholipase D phosphatidylcholine phosphatidic acid pathway and tyrosine kinases


id: cord-015859-5kt59ose
type: CHEMICAL
entity:
  ACE gene is located on chromosome 17 Somatic ACE has 2 homologous domains which share 60 sequence homology Both domains contain a catalytically active site Wei et al 1991a and are situated at the N and C terminal side of ACE According to their position


id: cord-007707-c38fu1jv
type: DISEASE
entity:
  human immunodeficiency virus HIV 1 parvovirus B19 cytomegalovirus CMV hepatitis B virus HBV and hepatitis C virus HCV


id: cord-291595-8241pjpe
type: PROTEIN
entity:
  granulocyte colony stimulating factor G CSF interferon gammainduced protein 10 IP10 monocyte chemoattractant protein 1 MCP1 macrophage inflammatory protein 1alpha MIP1A


id: cord-291595-8241pjpe
type: GGP
entity:
  Cytokine DOI 10 1016 j cyto 2020 155151 sha 9d990a819a91575a7590bac9cb0e2f32a092e6b9 doc_id 291595 cord_uid 8241pjpe


id: cord-291595-8241pjpe
type: GGP
entity:
  human angiotensin converting enzyme related carboxypeptidase COVID 19 interactions with angiotensin converting enzyme


id: cord-298490-p1msabl5
type: ORG
entity:
  the American College of Cardiology American Heart Association American Society of Hypertension and European Heart Association


id: cord-018009-8j40876m
type: ORG
entity:
  the American College of Cardiology American Heart Association Task Force on Practice Guidelines Committee


id: cord-313664-qq0h68vc
type: GGP
entity:
  Ang 1 7 AT2R angiotensin type 2 receptor AT1R angiotensin type 1 receptor IRAP insulin regulated aminopeptidase Ang IV receptor AMPA aminopeptidase A AMPM aminopeptidase M ACE angiotensin converting enzyme ACE2 angiotensin converting enzyme


id: cord-278265-hgggkr5y
type: GGP
entity:
  ACE i angiotensin converting enzyme inhibitor ARB angiotensin receptor blocker BUN blood urea nitrogen Cr creatinine eGFR


id: cord-252193-pgr07l9b
type: PROTEIN
entity:
  interest Angiotensin Converting Enzyme 2 AT1RAngiotensin Type 1 Receptor RAS Renin Angiotensin System TGF β Transforming Growth Factor


id: cord-276192-sgts963l
type: PROTEIN
entity:
  Ang IV Ang I angiotensin I Ang II angiotensin II Ang III angiotensin III Ang IV angiotensin IV Ang 1 9 angiotensin 1 9 Ang 1 7 angiotensin 1 7


id: cord-276192-sgts963l
type: PROTEIN
entity:
  Enzyme NEP neutral endopeptidase ACE angiotensin converting enzyme AD aspartate decarboxylase APA aminopeptidase A


id: cord-276192-sgts963l
type: GGP
entity:
  Ang IV Ang I angiotensin I Ang II angiotensin II Ang III angiotensin III Ang IV angiotensin IV Ang 1 9 angiotensin 1 9 Ang 1 7 angiotensin 1 7 Ang A angiotensin A ACE2


id: cord-276192-sgts963l
type: DISEASE
entity:
  cardiovascular kidney immune and neural homeostasis 14 Metabolic pathways of the classical RAAS axis


id: cord-311099-59pnm4fn
type: CHEMICAL
entity:
  angiotensin 1 7 metabolism in pulmonary and renal tissues Angiotensin 1 7 reduces bile duct proliferation and hepatic fibrosis


id: cord-317888-ei598viq
type: GGP
entity:
  ACE2 angiotensinconverting enzyme 2 Ang angiotensin ARB angiotensin II type 1 receptor blockers AT1R angiotensin II type 1 receptor AT2R angiotensin II type 2 receptor


id: cord-273136-hrgtaunt
type: PROTEIN
entity:
  Renin Angiotensin System RAS DOI 10 1016 b978 0 12 801364 9 00022 5 sha ec1385d8356cf57df6df25a5aa247ebdab148b91 doc_id 273136 cord_uid hrgtaunt The


id: cord-309619-glb2y82u
type: CELL_TYPE
entity:
  endothelial cells pericytes vascular smooth muscle cells macrophages fibroblasts T cells cardiomyocytes


id: cord-309619-glb2y82u
type: PROTEIN
entity:
  Tumor necrosis factor alpha IL 10 Interleukin 10 MCP 1 Macrophage chemoattractant protein 1 MIP 1A Macrophage inhibitory protein 1A IL 6 Interleukin 6 IL 1b Interleukin 1 beta NF KB nuclear factor kappa B inflammatory protein MIP 1A


id: cord-309619-glb2y82u
type: PROTEIN
entity:
  ACE2 Angiotensin converting enzyme 2 SARS CoV 2 Severe acute respiratory syndrome coronavirus 2 Ang II Angiotensin II


id: cord-309619-glb2y82u
type: GGP
entity:
  TMPRSS2 type II transmembrane serine protease TNF a tumor necrosis alpha TRAF3 TNF receptor associated factor 3


id: cord-309619-glb2y82u
type: CL
entity:
  vascular smooth muscle cells macrophages fibroblasts T cells cardiomyocytes enterocytes basal cell epidermal cells


id: cord-333580-tw9cehxv
type: GGP
entity:
  Syndr DOI 10 1016 j dsx 2020 07 041 sha c8b30bc9619e5b6cf908eebaa2b5edf0a65bce65 doc_id 333580 cord_uid tw9cehxv nan Dear Sir I


id: cord-277766-rxmpi61o
type: CHEBI
entity:
  l angiotensine 2 angiotensine 1 MAS l AC2 contrebalance l effet vasoconstricteur prolifératif fibrosant et pro inflammatoire


id: cord-277766-rxmpi61o
type: CHEMICAL
entity:
  tetrapeptide N acetyl Ser Asp Lys Pro on the G1 S transition of rat hepatocytes The tetrapeptide AcSDKP


id: cord-277766-rxmpi61o
type: CHEMICAL
entity:
  angiotensinconverting enzyme 2 ACE2 gene polymorphisms with parameters of left ventricular hypertrophy


id: cord-299960-ounktxxv
type: GGP
entity:
  dodecapeptide angiotensin 1 2 3 4 5 6 7 8 9 10 11 12 Ang 1 2 3 4 5 6 7 8 9 10 11 12 rat sequence Asp 1 Arg 2 Val 3 Tyr 4 Ile 5 His 6 Pro 7 Phe 8 His 9 Leu


id: cord-303394-iqepytyd
type: GGP
entity:
  Appl Pharmacol DOI 10 1016 j taap 2010 02 009 sha 52ef40cbfbd93f506eb4d57a15a7fac62a43e778 doc_id 303394 cord_uid iqepytyd


id: cord-291137-09a3tblt
type: GGP
entity:
  bradykinin 1 2 3 4 5 ACE indicates angiotensin converting enzyme Ang 1 angiotensin I Ang 2 angiotensin II AT 1 angiotensin type 1


id: cord-291137-09a3tblt
type: GGP
entity:
  angiotensinconverting enzyme Ang 1 7 angiotensin 1 7 Ang 1 9 angiotensin 1 9 Ang 1 angiotensin I Ang 2 angiotensin II


id: cord-318327-9sh2eksm
type: CELL_LINE
entity:
  rat brush border epithelial cells lamina propria muscularis mucosa submucosal blood vessels and muscularis propria 77 Angiotensinogen mRNA


id: cord-318327-9sh2eksm
type: GGP
entity:
  endopeptidase Am aminopeptidase AT1R angiotensin type 1 receptor AT2R angiotensin type 2 receptor AT4R angiotensin type 4 receptor PRR pro renin receptor water


id: cord-023225-5quigar4
type: PROTEIN
entity:
  Glycyl tRNA Synthetase S R Stone 1 K Hoffmann 1 2 N Milech 1 2 P T Cunningham 1 M Kerfoot 1 S Winslow 1 Y F Tan 1 M Anastasas 1 C Hall 1 M Scobie 1 P Watt 2 and R Hopkins 1 2 1 Drug Discovery Technology Unit Telethon Institute for Child Health Research 100 Roberts Road Subicao 6008 Western Australia 2 Phylogica Pty Ltd 100 Roberts Road Subiaco 6008 Western Australia Biopanning


id: cord-023225-5quigar4
type: PROTEIN
entity:
  linear covalent structure Ac Aib Asn Leu Aib Pro Ala Val Aib Pro Aib Leu Aib Pro Leuol Ac acetyl Aib


id: cord-023225-5quigar4
type: PROTEIN
entity:
  Leishmania major C Servis H Zalila I Gonzalez L Lozano N Fasel Department of Biochemistry University of Lausanne


id: cord-023225-5quigar4
type: GGP
entity:
  S S Ac Ser ΨH CF3 Pro NHMe and R S Ac Ser Ψ CF3 HPro NHMe 4 Their thermodynamic and kinetic features


id: cord-023225-5quigar4
type: ORG
entity:
  A Girard E Biron Faculty of Pharmacy Université Laval and CHUQ Research Center Quebec Canada Combinatorial


id: cord-023225-5quigar4
type: ORG
entity:
  Haute Normandie PRIMACEN Institute for Medical Research and Innovation IRIB University of Rouen 76821


id: cord-023225-5quigar4
type: CHEMICAL
entity:
  betaamyloid toxicity 1 2 Aggregated βA causes many pathological changes in cultures of mixed neurons and astrocytes such as sporadic cytoplasmic intracellular Ca 2 signal activation of reactive oxygen


id: cord-023225-5quigar4
type: CHEMICAL
entity:
  N terminal extremity 1 probably this insertion on another portion of the peptide provides a change in the conformation of the molecule and its hydrophobic cluster


id: cord-023225-5quigar4
type: CHEMICAL
entity:
  N N isopropylidene derivatives of Ser Thr containing dipeptides 3 We found the reaction of mannopyranosyl trichloroacetimidate


id: cord-277669-uujny2dm
type: SO
entity:
  domain NT proBNP N terminal pro B type natriuretic peptide PAI 1 plasminogen activator inhibitor type


id: cord-277669-uujny2dm
type: WORK_OF_ART
entity:
  Short Term Outcome and Risk Factors for Adverse Clinical Outcomes in Adults With Severe Acute Respiratory Syndrome SARS Prevalence of Comorbidities in the Middle East Respiratory Syndrome Coronavirus


id: cord-277669-uujny2dm
type: ORG
entity:
  the Cardiovascular System Implications for Risk Assessment Diagnosis and Treatment Options Clinical Course and Risk Factors for Mortality of Adult Inpatients With COVID 19


id: cord-277669-uujny2dm
type: ORG
entity:
  the Joint European Society of Cardiology ESC American College of Cardiology ACC American Heart Association


id: cord-277669-uujny2dm
type: ORG
entity:
  the Cardiovascular System From Basic Science to Clinical Implications Renin Angiotensin Aldosterone Inhibition


id: cord-277669-uujny2dm
type: EVENT
entity:
  Human Juxtaposing Population Groups Gender and Different Tissues Molecular Simulation of SARS CoV 2 Spike Protein Binding


id: cord-277669-uujny2dm
type: ORG
entity:
  Human ACE2 Natural Variants Reveals Altered Susceptibility to Infection Human ACE2 Receptor Polymorphisms


id: cord-277669-uujny2dm
type: ORG
entity:
  the Human ACE2 Gene to Weaken the Interaction of the ACE2 Receptor With the SARS CoV 2 S Protein Association


id: cord-277669-uujny2dm
type: PRODUCT
entity:
  the Renin Angiotensin System in Heart Failure Eccentric Overload Muscle Damage Is Attenuated By a Novel Angiotensin 1 7 Treatment Synthesis and Actions of an Innovative Bispecific Designer Peptide


id: cord-326223-q6e60nf8
type: DNA
entity:
  rat and rabbit nephron Novel angiotensin peptides Counterregulatory actions of angiotensin 1 7 Angiotensin 1 7


id: cord-314102-8jf3fnqe
type: GGP
entity:
  mouse angiotensin converting enzyme related carboxypeptidase mACE2 Tumor necrosis factor α convertase ADAM17


id: cord-343736-htwlfqos
type: DNA
entity:
  H5N1 influenza viral protein coding genes hemagglutinin neuraminidase NA nonstructural protein 1 NS1 nonstructural protein 2 NS2 polymerase complex PA polymerase complex PB1 polymerase complex PB2 M1 matrix protein 2 M2


id: cord-349445-yh6ndtgm
type: PROTEIN
entity:
  Transforming Growth Factor β1 Induced Endothelial To Mesenchymal Transition and Tissue Fibrosis by Endothelin 1 ET 1 A


id: cord-349445-yh6ndtgm
type: PROTEIN
entity:
  Angiotensin Converting Enzyme 2 Angiogenesis 1 7 Mas Axis Confers Cardiopulmonary Protection against Lung Fibrosis and Pulmonary Hypertension


id: cord-349445-yh6ndtgm
type: GGP
entity:
  ACE 2 Angiotensin converting enzyme 2 Ang 1 7 Angiotensin AT 1 Angiotensin II type 1 receptor ET 1 Endothelin 1 fMLP


id: cord-349445-yh6ndtgm
type: ORG
entity:
  Interleukin 6 Induces Oxidative Stress and Endothelial Dysfunction by Overexpression of the Angiotensin II Type 1 Receptor Endothelium


id: cord-349445-yh6ndtgm
type: ORG
entity:
  Structural Substrate Conditions Required for Neutral Endopeptidase Mediated Natriuretic Peptide Degradation


id: cord-349445-yh6ndtgm
type: LAW
entity:
  ARNIs COVID 19 Treatment Close to a Cure A Rapid Review of Pharmacotherapies for the Novel Coronavirus Risks Related to the Use of Non Steroidal Anti Inflammatory Drugs in Community Acquired Pneumonia in Adult and Pediatric Patients


id: cord-337678-vh6dpf4e
type: GGP
entity:
  Bartter s and Gitelman s syndrome patients Angiotensin converting enzyme inhibitors angiotensin II type 1 receptor blockers


id: cord-322212-8xrehbd1
type: PROTEIN
entity:
  ACE angiotensin converting enzyme ACE2 angiotensin converting enzyme 2 Ang 2 angiotensin II COVID 19 coronavirus disease 2019 SARS


id: cord-259933-ggx4v0bz
type: ORG
entity:
  the Chinese Preventive Medicine Association Korean Society for Antimicrobial Therapy Korean Society for Healthcare associated Infection Control and Prevention Clinical


id: cord-344012-npob20n0
type: CHEMICAL
entity:
  angiotensin 1 7 levels respectively Our review summarizes the progress over the past 20 years highlighting


id: cord-334717-zg9f19p8
type: PROTEIN
entity:
  AT1 R angiotensin 1 receptor AT2 R angiotensin 2 receptor Mas1 R mitochondrial assembly receptor ACEI angiotensin converting enzyme


id: cord-334717-zg9f19p8
type: PROTEIN
entity:
  AT1 R angiotensin 1 receptor Mas1 R mitochondrial assembly receptor ACEI angiotensin converting enzyme


id: cord-334717-zg9f19p8
type: GGP
entity:
  ACE2 Ang I angiotensin I Ang II angiotensin II Ang 1À7 angiotensin 1À7 ACE angiotensin converting enzyme ACE 2 angiotensin converting enzyme 2 AT1 R angiotensin 1 receptor AT2 R angiotensin 2 receptor Mas1 R mitochondrial assembly receptor ACEI angiotensin converting enzyme inhibitor ARB angiotensin 1 receptor blocker


id: cord-334717-zg9f19p8
type: GGP
entity:
  ACE angiotensin converting enzyme ACE 2 angiotensin converting enzyme 2 AT1 R angiotensin 1 receptor Mas1 R mitochondrial assembly receptor ACEI angiotensin converting enzyme inhibitor ARB angiotensin 1 receptor blocker TMPRSS2 transmembrane protein serine protease 2


id: cord-343225-8nxsrod5
type: WORK_OF_ART
entity:
  2 Recombinant Expression and Characterization of Human and Murine ACE2 Species Specific Activation of the Alternative Renin Angiotensin System Regulation


id: cord-342478-2k2eb1rk
type: ORG
entity:
  the Louisiana State University Health Sciences Center 3450 Institutional Animal Care and Use Committee


id: cord-307894-pfsztifl
type: GGP
entity:
  ACE2 apelin bradykinin carboxypeptidase cardiovascular collectrin renin angiotensin system SARS virus


id: cord-339752-o6atz33c
type: WORK_OF_ART
entity:
  The Key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID 19 Demon or Angel


id: cord-320331-wtxja5i9
type: CELL_TYPE
entity:
  esophageal epithelial cells enterocytes male reproductive cells type II lung alveolar epithelial cells renal tubules ductal cells bladder urothelial cells endothelial cells


id: cord-320331-wtxja5i9
type: PROTEIN
entity:
  growth factor 2 receptor IGF2R angiotensinogen AGT epidermal growth factor receptor EGFR matrix metalloendopeptidase MME alanyl aminopeptidase


id: cord-320331-wtxja5i9
type: GGP
entity:
  growth factor 2 receptor IGF2R angiotensinogen AGT epidermal growth factor receptor EGFR matrix metalloendopeptidase MME alanyl aminopeptidase ANPEP


id: cord-320331-wtxja5i9
type: WORK_OF_ART
entity:
  The Effects of ARBs ACEis and Statins on Clinical Outcomes of COVID 19 Infection Among Nursing Home Residents


id: cord-352004-0mdh1jmo
type: WORK_OF_ART
entity:
  The Role of ACE2 in Pulmonary Diseases Relevance for the Nephrologist Association of angiotensin converting enzyme


# bib

id: cord-000072-2ygb80sc
title: Bench-to-bedside review: Angiopoietin signalling in critical illness – a future target?
author: van Meurs, Matijs
date: 2009-03-09
txt: ./txt/cord-000072-2ygb80sc.txt
cache: ./cache/cord-000072-2ygb80sc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689450/
doi: 10.1186/cc7153
summary:
  All three functions are involved in MODS, in which ECs are shed, blood flow regulation is hampered, vessels become leaky, cells migrate out of the vessel and into the surrounding tissue, and coagulation and inflammation pathways are activated [16] . The Ang/Tie system, which was discovered after vascular endothelial growth factor (VEGF) and its receptors, is mainly restricted to EC regulation and is the focus of this review. In sepsis, VEGF and its soluble receptor sFLT-1 (soluble VEGFR-1) are also increased in a disease severity-dependent manner [40] [41] [42] .The picture that emerges from these studies is that the Ang/Tie signalling system appears to play a crucial role in the symptoms of MODS. Ang-2 acts as an antagonist of Ang-1, stops Tie2 signalling, and sensitizes endothelium to inflammatory mediators (for example, tumour necrosis factor-α) or facilitates vascular endothelial growth factor-induced angiogenesis. Hypoxia and vascular endothelial growth factor acutely up-regulate angiopoietin-1 and Tie2 mRNA in bovine retinal pericytes

abstract:
  Multiple organ dysfunction syndrome (MODS) occurs in response to major insults such as sepsis, severe haemorrhage, trauma, major surgery and pancreatitis. The mortality rate is high despite intensive supportive care. The pathophysiological mechanism underlying MODS are not entirely clear, although several have been proposed. Overwhelming inflammation, immunoparesis, occult oxygen debt and other mechanisms have been investigated, and – despite many unanswered questions – therapies targeting these mechanisms have been developed. Unfortunately, only a few interventions, usually those targeting multiple mechanisms at the same time, have appeared to be beneficial. We clearly need to understand better the mechanisms that underlie MODS. The endothelium certainly plays an active role in MODS. It functions at the intersection of several systems, including inflammation, coagulation, haemodynamics, fluid and electrolyte balance, and cell migration. An important regulator of these systems is the angiopoietin/Tie2 signalling system. In this review we describe this signalling system, giving special attention to what is known about it in critically ill patients and its potential as a target for therapy.


id: cord-000570-0qkzd2w4
author: Ferreira, Anderson J.
date: 2012-01-26
txt: ./txt/cord-000570-0qkzd2w4.txt
cache: ./cache/cord-000570-0qkzd2w4.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272817/
doi: 10.1155/2012/147825
summary:
  Thus, now it is recognized that the ACE2/Ang-(1-7)/Mas axis is present in vascular endothelial cells and modulates its function promoting vasorelaxation [82] , reduction of the oxidative stress [83, 84] , and antiproliferative effects [85, 86] . Indeed, the important role of the RAS in the lung pathophysiology and the side effects and pulmonary toxicity induced by the ACEi raised the interest to evaluate the activation of the ACE2/Ang-(1-7)/Mas axis as an alternative target to treat pulmonary pathologies. Taking into account that systemic hypotension is an important limitation to the use of ACEi and ARBs in pulmonary patients, therapies based on the ACE2/Ang-(1-7)/Mas axis emerge as a safe and efficient approach since studies using the ACE2 activator XNT or ACE2 gene transfer have shown that these strategies induce beneficial pulmonary outcome without changes in systemic blood pressure in rats and mice [39, 117, 118] .

title:
  New Cardiovascular and Pulmonary Therapeutic Strategies Based on the Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas Receptor Axis

abstract:
  Angiotensin (Ang)-(1–7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). The discovery of the angiotensin-converting enzyme homologue ACE2 revealed important metabolic pathways involved in the Ang-(1–7) synthesis. This enzyme can form Ang-(1–7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1–9) with subsequent Ang-(1–7) formation. Additionally, it is well established that the G protein-coupled receptor Mas is a functional ligand site for Ang-(1–7). The axis formed by ACE2/Ang-(1–7)/Mas represents an endogenous counter regulatory pathway within the RAS whose actions are opposite to the vasoconstrictor/proliferative arm of the RAS constituted by ACE/Ang II/AT(1) receptor. In this review we will discuss recent findings concerning the biological role of the ACE2/Ang-(1–7)/Mas arm in the cardiovascular and pulmonary system. Also, we will highlight the initiatives to develop potential therapeutic strategies based on this axis.


id: cord-001961-0ic7twhy
author: Ding, Dan
date: 2015-09-26
txt: ./txt/cord-001961-0ic7twhy.txt
cache: ./cache/cord-001961-0ic7twhy.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762923/
doi: 10.1007/s00109-015-1343-6
summary:
  In addition to lower blood pressure, ATRQβ-001 vaccination ameliorated biochemical parameter changes of renal dysfunction, mesangial expansion, and fibrosis through inhibiting oxidative stress, macrophage infiltration, and proinflammatory factor expression. Furthermore, ATRQβ-001 vaccination suppressed renal Ang II-AT1R activation and abrogated the downregulation of angiotensin-converting enzyme 2-Ang (1–7), similar to olmesartan treatment, while no obvious feedback activation of circulating or local renin-angiotensin system (RAS) was only observed in vaccine group. In conclusion, the ATRQβ-001 vaccine ameliorated streptozotocin-induced diabetic renal injury via modulating two RAS axes and inhibiting TGF-β1/Smad3 signal pathway, providing a novel, safe, and promising method to treat diabetic nephropathy. Recently, we developed a therapeutic hypertensive vaccine ATRQβ-001, a peptide (ATR-001) derived from human Ang II receptor type 1 (AT1R) conjugated with Qβ bacteriophage virus-like particles, which decreased the blood pressure of hypertensive animals effectively through diminishing the pressure response and inhibiting signal transduction initiated by Ang II with no obvious feedback activation of circulating or local RAS [11] .

title:
  Vaccination against type 1 angiotensin receptor prevents streptozotocin-induced diabetic nephropathy

abstract:
  ABSTRACT: Recently, our group has developed a therapeutic hypertensive vaccine against angiotensin (Ang) II type 1 receptor (AT1R) named ATRQβ-001. To explore its potential effectiveness on streptozotocin-induced diabetic nephropathy, male Sprague Dawley rats were randomly divided into two groups: a control and a diabetic model. After 1 week, the diabetic rats were divided into four subgroups (each with 15 rats) for 14-week treatments with saline, olmesartan, ATRQβ-001, and Qβ virus-like particle (VLP), respectively. In addition to lower blood pressure, ATRQβ-001 vaccination ameliorated biochemical parameter changes of renal dysfunction, mesangial expansion, and fibrosis through inhibiting oxidative stress, macrophage infiltration, and proinflammatory factor expression. Furthermore, ATRQβ-001 vaccination suppressed renal Ang II-AT1R activation and abrogated the downregulation of angiotensin-converting enzyme 2-Ang (1–7), similar to olmesartan treatment, while no obvious feedback activation of circulating or local renin-angiotensin system (RAS) was only observed in vaccine group. In rat mesangial cells, the anti-ATR-001 antibody inhibited high glucose-induced transforming growth factor-β1 (TGF)-β1/Smad3 signal pathway. Additionally, no significant immune-mediated damage was detected in vaccinated animals. In conclusion, the ATRQβ-001 vaccine ameliorated streptozotocin-induced diabetic renal injury via modulating two RAS axes and inhibiting TGF-β1/Smad3 signal pathway, providing a novel, safe, and promising method to treat diabetic nephropathy. KEY MESSAGES: Overactivation of RAS plays a crucial role in the development of the DN. Our aim was to verify the effectiveness of ATRQβ-001 vaccine in STZ-induced DN. The ATRQβ-001 modulated two RAS axes and inhibited TGF-β1/Smad3 signal pathway. The vaccine therapy may provide a novel, safe, and promising method to treat DN. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00109-015-1343-6) contains supplementary material, which is available to authorized users.


id: cord-001982-arczqdza
title: Anti-Inflammatory Action of Angiotensin 1-7 in Experimental Colitis
author: Khajah, Maitham A.
date: 2016-03-10
txt: ./txt/cord-001982-arczqdza.txt
cache: ./cache/cord-001982-arczqdza.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786309/
doi: 10.1371/journal.pone.0150861
summary:
  It is thought that the beneficial effects of ACE-inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on blood pressure control and in delaying/inhibiting the cardiac remodeling process is through increasing serum levels of Ang1-7 [9] [10] [11] [12] . A seven fold decrease in the plasma level of Ang 1-7 was demonstrated in DSS treated mice compared to untreated (UT) group at day 7 post colitis induction (Fig 1A) . The level of phosphorylated forms of three key signaling intermediates, ERK1/2 (Fig 8) , p38 MAPK (Fig 9) and Akt (Fig 10) , were measured by immunofluorescence in sections from resected colon tissue of untreated mice or mice treated with DSS (for 7 days) plus daily Ang 1-7 or saline (vehicle) treatment.

abstract:
  BACKGROUND: There is evidence to support a role for angiotensin (Ang) 1–7 in reducing the activity of inflammatory signaling molecules such as MAPK, PKC and SRC. Enhanced angiotensin converting enzyme 2 (ACE2) expression has been observed in patients with inflammatory bowel disease (IBD) suggesting a role in its pathogenesis, prompting this study. METHODS: The colonic expression/activity profile of ACE2, Ang 1–7, MAS1-receptor (MAS1-R), MAPK family and Akt were determined by western blot and immunofluorescence. The effect of either exogenous administration of Ang 1–7 or pharmacological inhibition of its function (by A779 treatment) was determined using the mouse dextran sulfate sodium model. RESULTS: Enhanced colonic expression of ACE2, Ang1-7 and MAS1-R was observed post-colitis induction. Daily Ang 1–7 treatment (0.01–0.06 mg/kg) resulted in significant amelioration of DSS-induced colitis. In contrast, daily administration of A779 significantly worsened features of colitis. Colitis-associated phosphorylation of p38, ERK1/2 and Akt was reduced by Ang 1–7 treatment. CONCLUSION: Our results indicate important anti-inflammatory actions of Ang 1–7 in the pathogenesis of IBD, which may provide a future therapeutic strategy to control the disease progression.


id: cord-002307-gk84fnb9
author: Kehoe, Patrick Gavin
date: 2016-11-25
txt: ./txt/cord-002307-gk84fnb9.txt
cache: ./cache/cord-002307-gk84fnb9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123239/
doi: 10.1186/s13195-016-0217-7
summary:
  METHODS: We measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores. ACE-2 enzyme activity is reduced in Alzheimer''s disease in association with increasing Aβ load and tau pathology ACE-2 activity was significantly reduced by approximately 50% in the mid-frontal cortex in AD compared with age-matched controls (P < 0.0001) (Fig. 1a) . Together, these data strongly suggest that reduced ACEFig. 2 Angiotensin-converting enzyme 2 (ACE-2) activity is reduced in association with apolipoprotein E (APOE) ε4 and ACE1 (rs1799752) indel polymorphism and increased in cerebral amyloid angiopathy (CAA).

title:
  Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology

abstract:
  BACKGROUND: Hyperactivity of the classical axis of the renin-angiotensin system (RAS), mediated by angiotensin II (Ang II) activation of the angiotensin II type 1 receptor (AT1R), is implicated in the pathogenesis of Alzheimer’s disease (AD). Angiotensin-converting enzyme-2 (ACE-2) degrades Ang II to angiotensin 1–7 (Ang ﻿﻿(1-7)) and counter-regulates the classical axis of RAS. We have investigated the expression and distribution of ACE-2 in post-mortem human brain tissue in relation to AD pathology and classical RAS axis activity. METHODS: We measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores. RESULTS: ACE-2 activity was significantly reduced in AD compared with age-matched controls (P < 0.0001) and correlated inversely with levels of Aβ (r = −0.267, P < 0.001) and phosphorylated tau (p-tau) pathology (r = −0.327, P < 0.01). ACE-2 was reduced in individuals possessing an APOE ε4 allele (P < 0.05) and was associated with ACE1 indel polymorphism (P < 0.05), with lower ACE-2 activity in individuals homozygous for the ACE1 insertion AD risk allele. ACE-2 activity correlated inversely with ACE-1 activity (r = −0.453, P < 0.0001), and the ratio of ACE-1 to ACE-2 was significantly elevated in AD (P < 0.0001). Finally, we show that the ratio of Ang II to Ang (1–7) (a proxy measure of ACE-2 activity indicating conversion of Ang II to Ang (1–7)) is reduced in AD. CONCLUSIONS: Together, our findings indicate that ACE-2 activity is reduced in AD and is an important regulator of the central classical ACE-1/Ang II/AT1R axis of RAS, and also that dysregulation of this pathway likely plays a significant role in the pathogenesis of AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-016-0217-7) contains supplementary material, which is available to authorized users.


id: cord-002632-6he8sjpf
author: Goldstein, Benjamin
date: 2017-07-16
txt: ./txt/cord-002632-6he8sjpf.txt
cache: ./cache/cord-002632-6he8sjpf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534309/
doi: 10.1155/2017/6914976
summary:
  There were a number of profound differences in the expression of the genes encoding the proteins comprising and closely associated with the renin-angiotensin system (RAS), between normal lung tissue and the lung tumor tissue (Figures 1 and 2 and Table 2 ). The gene expression for both Ang II receptor subtypes was dramatically reduced, 69 and 74%, respectively, ( Figure S1 ), for AT 1 and AT 2 in the lung tumor tissue ( < 0.01, corrected for multiple comparisons, Table 2 ). ACE, the gene that encodes the enzyme that converts the inactive precursor angiotensin I (Ang I) to the active hormone, Ang II, was expressed at a lower level and its expression was reduced by about half in the lung tumor tissue ( < 0.01 corrected for multiple comparisons Table 2 ).

title:
  Alterations in Gene Expression of Components of the Renin-Angiotensin System and Its Related Enzymes in Lung Cancer

abstract:
  OBJECTIVES: The study assessed the existence and significance of associations between the expression of fifteen renin-angiotensin system component genes and lung adenocarcinoma. MATERIALS AND METHODS: NCBI's built-in statistical tool, GEO2R, was used to calculate Student's t-tests for the associations found in a DNA expression study of adenocarcinoma and matched healthy lung tissue samples. The raw data was processed with GeneSpring™ and then used to generate figures with and without Sidak's multiple comparison correction. RESULTS: Ten genes were found to be significantly associated with adenocarcinoma. Seven of these associations remained statistically significant after correction for multiple comparisons. Notably, AGTR2, which encodes the AT(2) angiotensin II receptor subtype, was significantly underexpressed in adenocarcinoma tissue (p < 0.01). AGTR1, ACE, ENPEP, MME, and PRCP, which encode the AT(1) angiotensin II receptor, angiotensin-converting enzyme, aminopeptidase N, neprilysin, and prolylcarboxypeptidase, respectively, were also underexpressed. AGT, which encodes angiotensinogen, the angiotensin peptide precursor, was overexpressed in adenocarcinoma tissue. CONCLUSION: The results suggest an association between the expression of the genes for renin-angiotensin system-related proteins and adenocarcinoma. While further research is necessary to conclusively demonstrate a link between the renin-angiotensin system and lung cancers, the results suggest that the renin-angiotensin system plays a role in the pathology of adenocarcinoma.


id: cord-005931-iggkxbbf
title: Brain renin angiotensin in disease
author: Phillips, M. Ian
date: 2008-04-02
txt: ./txt/cord-005931-iggkxbbf.txt
cache: ./cache/cord-005931-iggkxbbf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095973/
doi: 10.1007/s00109-008-0331-5
summary:
  Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Taking the concept a step further, it was reasoned that if ANG II, formed by brain renin, was involved in hypertension, then inhibiting brain RAS would lower blood pressure. Minute injections of ANG II into key brain nuclei showed that ANG II could differentially produce pressor effects, elicit drinking, release vasopressin, inhibit the baroreflex, and increase sympathetic nervous system activity [20, 21] . In the double transgenic mice developed by Sigmund and colleagues [35] , to overexpress both human renin and human AGT so that they constantly have high ANG II levels, antisense to AT1R mRNA dramatically reduced the blood pressure. ACE-2, ANG (1-7), and Mas receptors are all localized in brain areas related to the control of cardiovascular function.

abstract:
  A brain renin angiotensin system (RAS) and its role in cardiovascular control and fluid homeostasis was at first controversial. This was because a circulating kidney-derived renin angiotensin system was so similar and well established. But, the pursuit of brain RAS has proven to be correct. In the course of accepting brain RAS, high standards of proof attracted state of the art techniques in all the new developments of biolo1gy. Consequently, brain RAS is a robust concept that has enlightened neuroscience as well as cardiovascular physiology and is a model neuropeptide system. Molecular biology confirmed the components of brain RAS and their location in the brain. Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Cre-lox delivery in vectors has enabled pinpoint gene deletion of brain RAS in discrete brain nuclei. The new concept of brain RAS includes ACE-2, Ang1–7, and prorenin and Mas receptors. Angiotensin II (ANG II) generated in the brain by brain renin has many neural effects. It activates behavioral effects by selective activation of ANG II receptor subtypes in different locations. It regulates sympathetic activity and baroreflexes and contributes to neurogenic hypertension. New findings implicate brain RAS in a much wider range of neural effects. We review brain RAS involvement in Alzheimer’s disease, stroke memory, and learning alcoholism stress depression. There is growing evidence to consider developing treatment strategies for a variety of neurological disease states based on brain RAS.


id: cord-006082-x1kankxd
title: Novel RAAS agonists and antagonists: clinical applications and controversies
author: Romero, Cesar A.
date: 2015-02-10
txt: ./txt/cord-006082-x1kankxd.txt
cache: ./cache/cord-006082-x1kankxd.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097622/
doi: 10.1038/nrendo.2015.6
summary:
  Despite the important improvements achieved with these agents in slowing the progression of established cardiorenal disease, the ACE inhibitors and the ARBs only provide a 20% reduction in the relative risk of Key points ■ Renin-angiotensin-aldosterone system (RAAS) blockade with an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker provides a 20% relative risk reduction for the progression of established cardiorenal disease compared with other non-RAAS blocking therapies ■ The RAAS is an endocrine, paracrine and autocrine system that regulates blood pressure homeostasis through effects on a variety of target organs, as well as having a role in the responses to vascular injury and repair ■ The RAAS is a complex system with a variety of sites suitable for pharmacological intervention ■ Novel molecules that alter the production of various RAAS peptides or that alter receptor density, function or responsiveness to these peptides could have an important influence on haemodynamics and vascular structure and function www.nature.com/nrendo progression of cardiovascular disease when compared with non-RAAS blocking therapy.

abstract:
  The renin–angiotensin–aldosterone system (RAAS) regulates blood pressure homeostasis and vascular injury and repair responses. The RAAS was originally thought to be an endocrine system critically important in regulating blood pressure homeostasis. Yet, important local forms of the RAAS have been described in many tissues, which are mostly independent of the systemic RAAS. These systems have been associated with diverse physiological functions, but also with inflammation, fibrosis and target-organ damage. Pharmacological modulation of the RAAS has brought about important advances in preventing morbidity and mortality associated with cardiovascular disease. Yet, traditional RAAS blockers such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) only reduce the risk of disease progression in patients with established cardiovascular or renal disease by ∼20% compared with other therapies. As more components of the RAAS are described, other potential therapeutic targets emerge, which could provide improved cardiovascular and renal protection beyond that provided by an ACE inhibitor or ARB. This Review summarizes the present and future pharmacological manipulation of this important system. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nrendo.2015.6) contains supplementary material, which is available to authorized users.


id: cord-006087-hynkb0a8
title: Ace revisited: A new target for structure-based drug design
author: Acharya, K. Ravi
date: 2003
txt: ./txt/cord-006087-hynkb0a8.txt
cache: ./cache/cord-006087-hynkb0a8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097707/
doi: 10.1038/nrd1227
summary:
  Current-generation angiotensin-converting enzyme (ACE) inhibitors are widely used for cardiovascular diseases, including high blood pressure, heart failure, heart attack and kidney failure, and have combined annual sales in excess of US $6 billion. Some differences in catalytic properties have been observed for these two sites: the N-domain site is notably 50-times more active toward the haemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) 21 , 1000-times Here, we provide an overview of ACE and the RAS, current ACE inhibitors and their clinical utility, insights from the tACE crystal structure, and the rationale and prospects for developing second-generation, domainselective inhibitors by structure-guided design. BPF was a mixture of peptides 59 , which were shown to be potent and specific inhibitors of ACE (TABLE 1), and structure-activity studies indicated that the optimal C-terminal inhibitory sequence was Phe-Ala-Pro 60 . An important caveat in considering the design and pharmacological utility of domain-selective ACE inhibitors is the potential for conformational effects that have not yet been observed in the tACE crystal structure.

abstract:
  Current-generation angiotensin-converting enzyme (ACE) inhibitors are widely used for cardiovascular diseases, including high blood pressure, heart failure, heart attack and kidney failure, and have combined annual sales in excess of US $6 billion. However, the use of these ACE inhibitors, which were developed in the late 1970s and early 1980s, is hampered by common side effects. Moreover, we now know that ACE actually consists of two parts (called the N- and C-domains) that have different functions. Therefore, the design of specific domain-selective ACE inhibitors is expected to produce next-generation drugs that might be safer and more effective. Here we discuss the structural features of current inhibitors and outline how next-generation ACE inhibitors could be designed by using the three-dimensional molecular structure of human testis ACE. The ACE structure provides a unique opportunity for rational drug design, based on a combination of in silico modelling using existing inhibitors as scaffolds and iterative lead optimization to drive the synthetic chemistry.


id: cord-006302-pnnkfid0
author: Ioakeimidou, A.
date: 2017-04-28
txt: ./txt/cord-006302-pnnkfid0.txt
cache: ./cache/cord-006302-pnnkfid0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101577/
doi: 10.1007/s10096-017-2988-6
summary:
  We studied the follow-up changes of circulating vasoactive peptides and cytokines until the improvement or the worsening of a patient and progression into specific organ dysfunctions. In a prospective study, concentrations of tumor necrosis factor-alpha (TNFα), interleukin (IL)-6, IL-8, IL-10, interferon-gamma (IFNγ), endocan and angiopoietin-2 (Ang-2) were measured in serum by an enzyme immunoassay in 175 patients at baseline; this was repeated within 24 h upon progression into new organ dysfunction (n = 141) or improvement (n = 34). Our aims were to monitor the changes of circulating levels of pro-inflammatory and antiinflammatory cytokines and of vasoactive peptides of critically ill patients at well-defined time-points of the clinical course and to understand how these changes mediate progression to organ dysfunction in an individualized way. When pair-wise comparisons between baseline and follow-up measurements were done within the subgroups of patients developing new organ dysfunctions, it was found that the only parameters significantly changing were endocan and Ang-2.

title:
  Increase of circulating endocan over sepsis follow-up is associated with progression into organ dysfunction

abstract:
  How circulating inflammatory mediators change upon sepsis progression has not been studied. We studied the follow-up changes of circulating vasoactive peptides and cytokines until the improvement or the worsening of a patient and progression into specific organ dysfunctions. In a prospective study, concentrations of tumor necrosis factor-alpha (TNFα), interleukin (IL)-6, IL-8, IL-10, interferon-gamma (IFNγ), endocan and angiopoietin-2 (Ang-2) were measured in serum by an enzyme immunoassay in 175 patients at baseline; this was repeated within 24 h upon progression into new organ dysfunction (n = 141) or improvement (n = 34). Endocan and Ang-2 were the only parameters that were significantly increased among patients who worsened. Any increase of endocan was associated with worsening with odds ratio 16.65 (p < 0.0001). This increase was independently associated with progression into acute respiratory distress syndrome (ARDS) as shown after logistic regression analysis (odds ratio 2.91, p: 0.002). Changes of circulating cytokines do not mediate worsening of the critically ill patients. Instead endocan and Ang2 are increased and this may be interpreted as a key-playing role in the pathogenesis of ARDS and septic shock. Any increase of endocan is a surrogate of worsening of the clinical course.


id: cord-006439-q7m4srvp
author: Nakagawa, Pablo
date: 2020-01-10
txt: ./txt/cord-006439-q7m4srvp.txt
cache: ./cache/cord-006439-q7m4srvp.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101821/
doi: 10.1007/s11906-019-1011-2
summary:
  Central administration of ANG-II elicits potent dipsogenic responses, induces sodium intake, triggers sympathetic outflow to the kidney and other organs, and recently, evidence has established that the brain RAS modulates metabolic function primarily through distinct nuclei within the hypothalamus [14] [15] [16] [17] . In the final section of this article, we will discuss how the development of state-of-the-art technology to study precise molecular signaling and neuronal circuits within the CNS are appropriate to elucidate the key mechanisms regulating generation and action of angiotensin peptides within different neuroanatomical regions. Intracerebroventricular infusion of ACE inhibitor prevents and reverses high blood pressure, demonstrating that production of ANG-II in the brain is required for DOCA-salt hypertension even though circulating RAS activity is suppressed [71] . Therefore, the development of novel drugs modulating the brain RAS might represent an effective solution to treat resistant hypertension coincident with elevated sympathetic activity and suppressed circulating renin activity.

title:
  The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation

abstract:
  PURPOSE OF THE REVIEW: The main goal of this article is to discuss how the development of state-of-the-art technology has made it possible to address fundamental questions related to how the renin-angiotensin system (RAS) operates within the brain from the neurophysiological and molecular perspective. RECENT FINDINGS: The existence of the brain RAS remains surprisingly controversial. New sensitive in situ hybridization techniques and novel transgenic animals expressing reporter genes have provided pivotal information of the expression of RAS genes within the brain. We discuss studies using genetically engineered animals combined with targeted viral microinjections to study molecular mechanisms implicated in the regulation of the brain RAS. We also discuss novel drugs targeting the brain RAS that have shown promising results in clinical studies and trials. SUMMARY: Over the last 50 years, several new physiological roles of the brain RAS have been identified. In the coming years, efforts to incorporate cutting-edge technologies such as optogenetics, chemogenetics, and single-cell RNA sequencing will lead to dramatic advances in our full understanding of how the brain RAS operates at molecular and neurophysiological levels.


id: cord-006553-0rmuvb5i
title: Characterization of Angiotensin Converting Enzyme-2 (ACE2) in Human Urine
author: Lew, Rebecca A.
date: 2006-05-05
txt: ./txt/cord-006553-0rmuvb5i.txt
cache: ./cache/cord-006553-0rmuvb5i.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102017/
doi: 10.1007/s10989-006-9031-6
summary:
  A soluble form of ACE, generated by proteolytic cleavage of the membrane-bound form, has been shown to be present in urine; although evidence for a similar release of ACE2 has been reported in cell culture, it is not yet known whether this occurs in vivo. Ang II is generated by two successive enzymatic steps: first, an inactive decapeptide (Ang I) is liberated from a liver-derived protein angiotensinogen by the aspartic protease renin in the circulation; the active eightresidue Ang II peptide is then formed by the action of the membrane-bound metallopeptidase, angiotensin converting enzyme (ACE). Like a number of membrane proteins, ACE has been shown to be proteolytically released from the cell surface (Parkin et al., 2004) , resulting in the presence of a catalytically active form circulating through the bloodstream, as well as in other biological fluids, including urine and seminal plasma (Hooper, 1991) .

abstract:
  Angiotensin converting enzyme-2 (ACE2) is a recently described membrane-bound carboxypeptidase identified by its homology to ACE, the enzyme responsible for the formation of the potent vasoconstrictor angiotensin II (Ang II). ACE2 inactivates Ang II and is thus thought to act in a counter-regulatory fashion to ACE. ACE2 is highly expressed in epithelial cells of distal renal tubules, and recent evidence indicates that expression is increased in a range of renal diseases. A soluble form of ACE, generated by proteolytic cleavage of the membrane-bound form, has been shown to be present in urine; although evidence for a similar release of ACE2 has been reported in cell culture, it is not yet known whether this occurs in vivo. The present study has identified ACE2 in human urine, both by a sensitive fluorescence-based activity assay and by Western immunoblot. Levels of ACE2 were surprisingly higher than ACE, which may reflect preferential targeting of the enzyme to the luminal surface of the renal epithelium. Future studies will determine whether increased expression of ACE2 in renal diseases are reflected in higher urinary levels of this novel enzyme.


id: cord-007267-r3gfr1gk
author: Kondo, Masateru
date: 2018-10-23
txt: ./txt/cord-007267-r3gfr1gk.txt
cache: ./cache/cord-007267-r3gfr1gk.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110082/
doi: 10.1093/ajh/hpy157
summary:
  CONCLUSIONS: Our results suggested that FEB ameliorates Ang II-induced aortic fibrosis via suppressing macrophage-derived TGF-β1 expression. In this study, we used a mouse model of hypertension induced by Ang II characterized by aortic fibrosis and macrophage accumulation 18 to investigate the effects of a XO inhibitor, FEB, on the pathogenesis of vascular remodeling independent of the level of uric acid. Our results suggested that FEB inhibited Ang II-induced transforming growth factor (TGF)-β1 expression in macrophages and suppressed fibrotic processes in aortae. These results suggested that the suppressive effects of FEB on Ang II-induced aortic fibrosis and blood pressure elevation were independent of the circulating uric acid level. the results indicating the suppressive effects of FEB on Ang II-induced macrophage-derived TGF-β1 mRNA expression. In the present study, we concluded that FEB suppressed Ang II-induced vascular fibrosis, via mainly inhibiting the TGF-β1 expression in the accumulated macrophages in the adventitia, as its additive effects outside of ameliorating hyperuricemia.

title:
  Xanthine Oxidase Inhibition by Febuxostat in Macrophages Suppresses Angiotensin II-Induced Aortic Fibrosis

abstract:
  BACKGROUND: Several reports from basic researches and clinical studies have suggested that xanthine oxidase (XO) inhibitors have suppressive effects on cardiovascular diseases. However, the roles of a XO inhibitor, febuxostat (FEB), in the pathogenesis of vascular remodeling and hypertension independent of the serum uric acid level remain unclear. METHODS: To induce vascular remodeling in mice, angiotensin II (Ang II) was infused for 2 weeks with a subcutaneously implanted osmotic minipump. FEB was administered every day during Ang II infusion. Aortic fibrosis was assessed by elastica van Gieson staining. Mouse macrophage RAW264.7 cells (RAW) and mouse embryonic fibroblasts were used for in vitro studies. RESULTS: FEB suppressed Ang II-induced blood pressure elevation and aortic fibrosis. Immunostaining showed that Ang II-induced macrophage infiltration in the aorta tended to be suppressed by FEB, and XO was mainly colocalized in macrophages, not in fibroblasts. Transforming growth factor-β1 (TGF-β1) mRNA expression was induced in the aorta in the Ang II alone group, but not in the Ang II + FEB group. Ang II induced α-smooth muscle actin-positive fibroblasts in the aortic wall, but FEB suppressed them. XO expression and activity were induced by Ang II stimulation alone but not by Ang II + FEB in RAW. FEB suppressed Ang II-induced TGF-β1 mRNA expression in RAW. CONCLUSIONS: Our results suggested that FEB ameliorates Ang II-induced aortic fibrosis via suppressing macrophage-derived TGF-β1 expression.


id: cord-007707-c38fu1jv
title: Role of Podocyte Injury in Glomerulosclerosis
author: Lu, Chen-Chen
date: 2019-06-19
txt: ./txt/cord-007707-c38fu1jv.txt
cache: ./cache/cord-007707-c38fu1jv.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7120923/
doi: 10.1007/978-981-13-8871-2_10
summary:
  Increased intracellular glucose could induce multiple cell and molecular events in podocyte: (1) generation of reactive oxygen species (ROS) and advanced glycation end products (AGEs), (2) increased flux of polyols and hexosamines, (3) activation of protein kinase C (PKC), (4) increased cytokines and growth factors, (5) aberrant Notch signaling, and (6) activate the renal RAS. High glucose induces generation of advanced glycation end products (AGEs) and reactive oxygen species (ROS), increased flux of polyols and hexosamines, increased activity of protein kinase C (PKC), upregulated expression of cytokines and growth factors including vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-β), induces aberrant Notch signaling, and activates the renal RAS (Anil Kumar et al. (2013) findings elaborated that Rac1/PAK1 signaling contributed to high glucose-induced podocyte EMT via promoting β-catenin and Snail transcriptional activities, which could be a potential mechanism involved in podocytes injury in response to stimuli under diabetic conditions.

abstract:
  Finding new therapeutic targets of glomerulosclerosis treatment is an ongoing quest. Due to a living environment of various stresses and pathological stimuli, podocytes are prone to injuries; moreover, as a cell without proliferative potential, loss of podocytes is vital in the pathogenesis of glomerulosclerosis. Thus, sufficient understanding of factors and underlying mechanisms of podocyte injury facilitates the advancement of treating and prevention of glomerulosclerosis. The clinical symptom of podocyte injury is proteinuria, sometimes with loss of kidney functions progressing to glomerulosclerosis. Injury-induced changes in podocyte physiology and function are actually not a simple passive process, but a complex interaction of proteins that comprise the anatomical structure of podocytes at molecular levels. This chapter lists several aspects of podocyte injuries along with potential mechanisms, including glucose and lipid metabolism disorder, hypertension, RAS activation, micro-inflammation, immune disorder, and other factors. These aspects are not technically separated items, but intertwined with each other in the pathogenesis of podocyte injuries.


id: cord-012747-s4wf0pix
title: Angiogenin and tRNA fragments in Parkinson’s disease and neurodegeneration
author: Prehn, Jochen H M
date: 2020-03-06
txt: ./txt/cord-012747-s4wf0pix.txt
cache: ./cache/cord-012747-s4wf0pix.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470775/
doi: 10.1038/s41401-020-0375-9
summary:
  Loss-of-function mutations in the angiogenin gene (ANG) have been initially discovered in familial cases of amyotrophic lateral sclerosis (ALS), however, variants in ANG have subsequently been identified in PD and Alzheimer''s disease. Stress-induced tRNA fragments have been proposed to have multiple cellular functions, including inhibition of ribosome biogenesis, inhibition of protein translation and inhibition of apoptosis. Subsequent studies showed that angiogenin exerts neuroprotective activities in vitro in models of excitotoxic, hypoxic and trophic factor-withdrawal-induced injury to motor neurons and other neural cells, including dopaminergic SH-SY5Y neuroblastoma cells [31, 36, 37] . demonstrated significantly decreased levels of endogenous angiogenin in an alpha-synuclein transgenic mouse model of PD and showed that recombinant human angiogenin protected against dopaminergic neuronal cell death and inhibited caspase-3 activation in neurotoxin-induced in vitro models of PD [49] . Identification of novel Angiogenin (ANG) gene missense variants in German patients with amyotrophic lateral sclerosis

abstract:
  In this review, we summarise the evidence for a role of the ribonuclease angiogenin in the pathophysiology of neurodegenerative disorders, with a specific focus on Parkinson’s disease (PD). Angiogenin is a stress-induced, secreted ribonuclease with both nuclear and cytosolic activities. Loss-of-function mutations in the angiogenin gene (ANG) have been initially discovered in familial cases of amyotrophic lateral sclerosis (ALS), however, variants in ANG have subsequently been identified in PD and Alzheimer’s disease. Delivery of angiogenin protein reduces neurodegeneration and delays disease progression in in vitro and in vivo models of ALS and in vitro models of PD. In the nucleus, angiogenin promotes ribosomal RNA transcription. Under stress conditions, angiogenin also translocates to the cytosol where it cleaves non-coding RNA into RNA fragments, in particular transfer RNAs (tRNAs). Stress-induced tRNA fragments have been proposed to have multiple cellular functions, including inhibition of ribosome biogenesis, inhibition of protein translation and inhibition of apoptosis. We will discuss recent evidence of tRNA fragment accumulation in PD, as well as their potential neuroprotective activities.


id: cord-015859-5kt59ose
title: Local Angiotensin Generation and AT(2) Receptor Activation
author: Esch, Joep H.M. Van
date: 2007
txt: ./txt/cord-015859-5kt59ose.txt
cache: ./cache/cord-015859-5kt59ose.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7119946/
doi: 10.1007/978-1-4020-6372-5_12
abstract: nan
summary:
  Mice lacking the ren-1 d gene are characterized by sexually dimorphic hypotension (leading to a significant reduction of blood pressure in female mice), absence of dense secretory/storage granule formation in juxta-glomerular cells, altered morphology of the kidney, and a significant increase of plasma prorenin levels (Clark et al 1997) . Importantly, binding of (pro)renin to the (pro)renin receptor in human mesangial cells also induced Ang II-independent effects, such as an increase in DNA synthesis, activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK)1 (p44)/ERK2 (p42), and plasminogenactivator inhibitor-1 release. AT 2 receptors are involved in physiological processes like development and tissue remodeling (by inhibiting cell growth and by stimulating apoptosis), regulation of blood pressure (vasodilatation), natriuresis and neuronal activity. In vitro studies using the isolated perfused rat Langendorff heart fully confirmed the idea of renin and angiotensinogen uptake underlying tissue angiotensin production.


id: cord-016335-z2movens
author: Ferrario, Carlos M.
date: 2010-06-15
txt: ./txt/cord-016335-z2movens.txt
cache: ./cache/cord-016335-z2movens.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7120586/
doi: 10.1007/978-1-59259-987-5_3
summary:
  There are few studies about the direct actions of Ang-(1-7) on heart function, although the peptide is highly expressed in rat myocardium (30) and can be detected in larger concentrations in the cardiac interstitium or the coronary sinus blood after acute coronary artery ligation (67) (68) (69) . That the heart may be an important site for Ang-(1-7) actions is highlighted by the demonstration that ACE activity in plasma and atrial tissue is inhibited by Ang-(1-7) (73) whereas the peptide enhances tritiated norepinephrine release from isolated atrial tissue at doses comparable to those for Ang II (74) . Indeed, immunocytochemical staining for the Ang-(1-7) receptor mas is evident in the afferent arteriole, as well as throughout the proximal tubules of the renal cortex providing biochemical support for the functional actions of the peptide (87) . The potential contribution of Ang-(1-7) to vascular control in pregnancy was also documented from increased vasodilator responses to the local application of the peptide in isolated small mesenteric arteries obtained from pregnant rats (102) .

title:
  Regulation of Cardiovascular Control Mechanisms by Angiotensin-(1–7) and Angiotensin-Converting Enzyme 2

abstract:
  Among the molecular forms of angiotensin peptides generated by the action of renin on angiotensinogen (Aogen), both angiotensin II (Ang II) and the amino terminal heptapeptide angiotensin-(1–7) [Ang-(1–7)] are critically involved in the long-term control of tissue perfusion, cell-cell communication, development, and growth. Whereas an impressive body of literature continues to uncover pleiotropic effects of Ang II in the regulation of cell function, research on Ang-(1–7) has a shorter history as it was only 16 yr ago that a biological function for this heptapeptide was first demonstrated in the isolated rat neuro-hypophysial explant preparation (1). On the contrary, the synthesis of angiotonin/ hypertensin (now Ang II) was first obtained in 1957 (2), three decades ahead of the discovery of Ang-(1–7) biological properties.


id: cord-017585-0llgr357
title: Role of ACE, ACE2 and Neprilysin in the Kidney
author: Chappell, Mark C.
date: 2007
txt: ./txt/cord-017585-0llgr357.txt
cache: ./cache/cord-017585-0llgr357.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122178/
doi: 10.1007/978-1-4020-6372-5_1
abstract: nan
summary:
  Although the emergence of receptor subtypes distinguishes the distinct signaling pathways of Ang II and Ang-(1-7), the post-renin enzymes that form and degrade these peptides must be considered in lieu of the overall regulation of the functional RAAS within the kidney. ACE, angiotensin converting enzyme; EPs, endopeptidases; NEP, neprilysin demonstration of endogenous levels of the peptide in the kidney, circulation and other tissues (Nagata et al 2006) . Thus, in addition to the proximal tubule epithelium, the glomerulus may be a second key site within the kidney where ACE2 may influence the local expression of angiotensin peptides and renal function. There are few studies on the regulation of the Ang-(1-7) receptor, although chronic ACE or AT 1 blockade reduced mas mRNA expression in the renal cortex of the Ren2 Lewis congenic rat .


id: cord-018009-8j40876m
title: ACE Inhibition in Heart Failure and Ischaemic Heart Disease
author: Campbell, Duncan J. John
date: 2007
txt: ./txt/cord-018009-8j40876m.txt
cache: ./cache/cord-018009-8j40876m.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122740/
doi: 10.1007/978-1-4020-6372-5_2
abstract: nan
summary:
  Angiotensin converting enzyme (dipeptidyl carboxypeptidase I, kininase II, EC 3.4.15.1, ACE) plays a major role in the metabolism of many different peptides, including angiotensin (Ang) I, bradykinin, kallidin, and N-acetyl-seryl-aspartyllysyl-proline (AcSDKP). Pooled analysis of the HOPE, EUROPA, and PEACE trials showed ACE inhibition reduced all cause and cardiovascular mortality, non-fatal myocardial infarction, stroke, heart failure, and coronary artery bypass surgery, leading to the recommendation that ACE inhibitors be considered in all patients with atherosclerosis (Dagenais et al 2006) . ACE inhibitor therapy did not increase either bradykinin or kallidin peptide levels in cardiac atria of patients with ischaemic heart disease, despite the reduction in Ang II levels . Bradykinin contributes to the systemic hemodynamic effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure Interaction between neutral endopeptidase and angiotensin converting enzyme inhibition in rats with myocardial infarction: effects on cardiac hypertrophy and angiotensin and bradykinin peptide levels Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure


id: cord-023225-5quigar4
title: Posters
author: nan
date: 2012-08-21
txt: ./txt/cord-023225-5quigar4.txt
cache: ./cache/cord-023225-5quigar4.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167970/
doi: 10.1002/psc.2449
abstract: No abstract is available for this article.
summary:
  To further explore the structure-function relationship, a viable synthesis strategy for pseudodesmin A analogues was developed, based on side-chain attachment of the first amino acid to the solid support, followed by stepwise Fmoc solid-phase synthesis of the linear peptide precursor and on-resin head-to-tail cyclization. The cases when the amino acid sequence of a fragment coincided with part of the primary structure of a natural oligopeptide were recorded in the Total protein chemical synthesis requires a case by case design and optimization which is governed by factors such as the solubility of the individual peptide segments, their primary sequence and in particular the presence of "difficult" amino acid residues at ligation junctions such as proline or the location of cysteines. In this study we present synthesis of two series of peptide libraries, which were designed by substitution of Leu in the P5, P6 position of our control peptide (Ac-LLLLRVKR-AMBA) with each of nineteen amino acid residues in order to verifying its influence on activity and selectivity of the resulting analogues.


id: cord-026680-ksacxsdk
author: Shoieb, Sherif M.
date: 2020-06-12
txt: ./txt/cord-026680-ksacxsdk.txt
cache: ./cache/cord-026680-ksacxsdk.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291180/
doi: 10.1007/s11010-020-03777-9
summary:
  Several reports demonstrated the direct contribution of cytochrome P450 1B1 (CYP1B1) enzyme and its associated cardiotoxic mid-chain, hydroxyeicosatetraenoic acid (HETEs) metabolites in the development of cardiac hypertrophy. 2,3′,4,5′-tetramethoxystilbene (TMS), a well-known CYP1B1 inhibitor, was able to significantly decrease the level of mid-chain HETEs and protect against angiotensin II (Ang II)-induced cardiac hypertrophy [17] . Therefore, the purpose of this study is to investigate whether resveratrol protects against Ang II-induced cellular hypertrophy through inhibition of CYP1B1/mid-chain HETEs mechanism. We examined whether different concentrations of resveratrol have a protective effect against Ang II-induced cellular hypertrophy through inhibiting the protein expression of CYP1B1. Resveratrol at concentration of 10 μM significantly inhibited Ang II-mediated increase of the metabolite formation rate of Fig. 4 Effect of resveratrol on mRNA expression and protein expression levels of CYP1B1 in H9c2 cells.

title:
  Resveratrol attenuates angiotensin II-induced cellular hypertrophy through the inhibition of CYP1B1 and the cardiotoxic mid-chain HETE metabolites

abstract:
  Several reports demonstrated the direct contribution of cytochrome P450 1B1 (CYP1B1) enzyme and its associated cardiotoxic mid-chain, hydroxyeicosatetraenoic acid (HETEs) metabolites in the development of cardiac hypertrophy. Resveratrol is commercially available polyphenol that exerts beneficial effects in wide array of cardiovascular diseases including cardiac hypertrophy, myocardial infarction and heart failure. Nevertheless, the underlying mechanisms responsible for these effects are not fully elucidated. Since resveratrol is a well-known CYP1B1 inhibitor, the purpose of this study is to test whether resveratrol attenuates angiotensin II (Ang II)-induced cellular hypertrophy through inhibition of CYP1B1/mid-chain HETEs mechanism. RL-14 and H9c2 cells were treated with vehicle or 10 μM Ang II in the absence and presence of 2, 10 or 50 μM resveratrol for 24 h. Thereafter, the level of mid-chain HETEs was determined using liquid chromatography–mass spectrometry (LC/MS). Hypertrophic markers and CYP1B1 gene expression and protein levels were measured using real-time PCR and Western blot analysis, respectively. Our results demonstrated that resveratrol, at concentrations of 10 and 50 μM, was able to attenuate Ang-II-induced cellular hypertrophy as evidenced by substantial inhibition of hypertrophic markers, β-myosin heavy chain (MHC)/α-MHC and atrial natriuretic peptide. Ang II significantly induced the protein expression of CYP1B1 and increased the metabolite formation rate of its associated mid-chain HETEs. Interestingly, the protective effect of resveratrol was associated with a significant decrease of CYP1B1 protein expression and mid-chain HETEs. Our results provided the first evidence that resveratrol protects against Ang II-induced cellular hypertrophy, at least in part, through CYP1B1/mid-chain HETEs-dependent mechanism.


id: cord-028640-kxrmzyo8
author: Wei, Wen-Ying
date: 2020-07-06
txt: ./txt/cord-028640-kxrmzyo8.txt
cache: ./cache/cord-028640-kxrmzyo8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338134/
doi: 10.1007/s11010-020-03802-x
summary:
  The Wnt/β-catenin agonist LiCl (1 mmol/kg) abolished the inhibitory effects of sFRP2 on cardiac hypertrophy and apoptosis, as evidenced by the increased cross-sectional area and LV collagen ratio and the deterioration of echocardiographic data. Our results demonstrated that sFRP2 overexpression retarded the development of cardiac hypertrophy and improved the deteriorative cardiac functions in AB-treated mice, as indicated by their reduced heart weight/body weight (HW/BW) ratio and decreased BNP mRNA expression (Fig. 2e-f ). As shown in Fig. 3e -g, sFRP2 mitigated Ang II-induced cardiomyocyte hypertrophy, which was indicated by a smaller cell surface area and decreased BNP mRNA expression compared with the positive control group. Our results showed that overexpression of sFRP2 significantly alleviated pressure-overload-induced myocardial hypertrophy via inhibition of the Wnt/β-catenin pathway. In our study, sFRP2 expression was decreased after hypertrophic stimuli both in vitro and in vivo, and overexpression of sFRP2 attenuated AB-induced apoptosis by inhibiting Wnt/β-catenin signaling.

title:
  Secreted frizzled-related protein 2 prevents pressure-overload-induced cardiac hypertrophy by targeting the Wnt/β-catenin pathway

abstract:
  BACKGROUND AND AIM: Secreted frizzled-related protein 2 (sFRP2) has been reported to be involved in cardiovascular diseases. However, its role in cardiac hypertrophy induced by pressure overload is still elusive. We aimed to examine the role of sFRP2 in the development of cardiac hypertrophy in vivo and in vitro. METHODS AND RESULTS: Following cardiac hypertrophy stimulated by aortic banding (AB), the expression of sFRP2 was downregulated in the hypertrophic ventricle. Adeno-associated virus 9 (AAV9) was injected through the tail vein to overexpress sFRP2 in the mouse myocardium. Overexpression of sFRP2 alleviated cardiomyocyte hypertrophy and interstitial fibrosis, as identified by the reduced cardiomyocyte cross-sectional area, heart weight/body weight ratio, and left ventricular (LV) collagen ratio. Additionally, sFRP2 decreased cardiomyocyte apoptosis induced by pressure overload. Western blot showed that sFRP2 prevented the expression of active β-catenin. The Wnt/β-catenin agonist LiCl (1 mmol/kg) abolished the inhibitory effects of sFRP2 on cardiac hypertrophy and apoptosis, as evidenced by the increased cross-sectional area and LV collagen ratio and the deterioration of echocardiographic data. CONCLUSION: Our study indicated that decreased sFRP2 levels were observed in failing mouse hearts. Overexpression of sFRP2 attenuated myocyte hypertrophy and interstitial fibrosis induced by hypertrophic stimuli by inhibiting the Wnt/β-catenin pathway. We revealed that sFRP2 may be a promising therapeutic target for the development of cardiac remodeling. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11010-020-03802-x) contains supplementary material, which is available to authorized users.


id: cord-252193-pgr07l9b
title: Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling
author: Sato, Teruki
date: 2019-01-09
txt: ./txt/cord-252193-pgr07l9b.txt
cache: ./cache/cord-252193-pgr07l9b.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/30634441/
doi: 10.3390/ijms20020239
summary:
  The loss of apelin increased the ratio of angiotensin-converting enzyme (ACE) to ACE2 expression in the Ang II-stressed hearts, and Ang II-induced cardiac fibrosis was markedly enhanced in apelin knockout mice. Wild type (WT) and apelin knockout (Apelin KO) mice at 12 months of age were continuously infused with either vehicle or angiotensin II (Ang II) for 2 weeks using osmotic minipumps (Ang II, 1 mg/kg/day) and measured for blood pressure using the tail-cuff method. While endogenous apelin antagonizes Ang II-induced heart pathology and upregulates ACE2 expression, it is interesting to observe that Ang II-stimulated elevation of blood pressure was not further increased in Apelin KO mice but comparable to WT mice. While endogenous apelin antagonizes Ang II-induced heart pathology and upregulates ACE2 expression, it is interesting to observe that Ang II-stimulated elevation of blood pressure was not further increased in Apelin KO mice but comparable to WT mice.

abstract:
  Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1–7-dependent manner. Whether apelin antagonizes the over-activation of the renin–angiotensin system in the heart remains elusive. In this study we show that the detrimental effects of angiotensin II (Ang II) were exacerbated in the hearts of aged apelin-gene-deficient mice. Ang II-mediated cardiac dysfunction and hypertrophy were augmented in apelin knockout mice. The loss of apelin increased the ratio of angiotensin-converting enzyme (ACE) to ACE2 expression in the Ang II-stressed hearts, and Ang II-induced cardiac fibrosis was markedly enhanced in apelin knockout mice. mRNA expression of pro-fibrotic genes, such as transforming growth-factor beta (TGF-β) signaling, were significantly upregulated in apelin knockout hearts. Consistently, treatment with the ACE-inhibitor Captopril decreased cardiac contractility in apelin knockout mice. In vitro, apelin ameliorated Ang II-induced TGF-β expression in primary cardiomyocytes, accompanied with reduced hypertrophy. These results provide direct evidence that endogenous apelin plays a crucial role in suppressing Ang II-induced cardiac dysfunction and pathological remodeling.


id: cord-259933-ggx4v0bz
title: The ACE-2 in COVID-19: Foe or Friend?
author: Dalan, Rinkoo
date: 2020-04-27
txt: ./txt/cord-259933-ggx4v0bz.txt
cache: ./cache/cord-259933-ggx4v0bz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32340044/
doi: 10.1055/a-1155-0501
summary:
  The SARS-CoV-2, a positive strand RNA virus, has been seen to infect humans through the angiotensin converting enzyme -2 (ACE-2) receptor [9] . In individuals with hypertension, diabetes, and other cardiovascular disorders with vascular complications, the renin angiotensin system (RAS) is known to be activated with an increase in ACE activity and a downregulation of ACE-2. Therefore, it may be assumed that the inherent downregulation of the ACE-2-Ang-(1-7)-Mas axis (as seen in metabolic conditions) is exacerbated in the COVID-19 state because (i) the virus uses the peptidase domain of the enzyme for entry into the cells and (ii) there is a decrease in ACE-2 with an increase in ACE [9] . Individuals with underlying hypertension, type 2 diabetes, or cardiovascular disease are at higher risk for respiratory failure and mortality in COVID-19.

abstract:
  COVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-AT (1) R axis and ACE-2-Ang-(1–7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-AT (1) R axis with a downregulation of ACE-2-Ang-(1–7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1–7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1–7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19.


id: cord-273136-hrgtaunt
title: Animal Models with a Genetic Alteration of the ACE2/Ang-(1-7)/Mas Axis
author: Rabelo, Luiza A.
date: 2015-04-24
txt: ./txt/cord-273136-hrgtaunt.txt
cache: ./cache/cord-273136-hrgtaunt.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/B9780128013649000225
doi: 10.1016/b978-0-12-801364-9.00022-5
summary:
  The aim of this chapter is to describe the animal models generated by transgenic technology for the functional analysis of the protective axis of the renin–angiotensin system, consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin (Ang)-(1-7), and Mas. Transgenic overexpression of the components of this axis in general led to an ameliorated cardiac and vascular damage in disease states and to an improved metabolic profile. 1, 2 The aim of this chapter is to describe the animal models generated by transgenic technology for the functional analysis of the protective axis of the RAS, consisting of angiotensin-converting enzyme 2 (ACE2), Ang-(1-7), and Mas. In biomedical research, the use of rats and mice has become a major tool, considering the easiness of breeding, growth, and maintenance and the similarity with human organisms in most cardiovascular and metabolic systems. Our group and others have developed several transgenic and KO rat and mouse models with genetic deletion and/or overexpression of components of the ACE2/Ang-(1-7)/Mas axis.

abstract:
  The aim of this chapter is to describe the animal models generated by transgenic technology for the functional analysis of the protective axis of the renin–angiotensin system, consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin (Ang)-(1-7), and Mas. Transgenic overexpression of the components of this axis in general led to an ameliorated cardiac and vascular damage in disease states and to an improved metabolic profile. Knockout models for ACE2 and Mas, however, show aggravated cardiovascular pathologies and a metabolic syndrome-like state. In particular, the local production of Ang-(1-7) in the vascular wall, in the heart, and in the brain was found to be of high physiological relevance by the use of transgenic animals overexpressing ACE2 or Ang-(1-7) in these tissues.


id: cord-273595-fkk4ry62
title: Potential influence of COVID-19/ACE2 on the female reproductive system
author: Jing, Yan
date: 2020-05-04
txt: ./txt/cord-273595-fkk4ry62.txt
cache: ./cache/cord-273595-fkk4ry62.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1093/molehr/gaaa030
doi: 10.1093/molehr/gaaa030
summary:
  2019-nCoV infects the target cell by binding to angiotensin-converting enzyme (ACE) 2 through its surface spike protein Zhou et al., 2020) , modulates the expression of ACE2 and causes severe injuries, similar to SARS-CoV (Kuba et al., 2005; Wang and Cheng, 2020) . ACE2 presents in stroma and granulosa cells as well as oocytes in immature rat ovaries, the expression of which is enhanced in antral and preovulatory follicles subjected to equine CG treatment (Pereira et al., 2009) . (2019) reported that activation of the ACE2/Ang-(1-7)/Mas axis in hypertensive pregnant rats could attenuate the cardiovascular dysfunction in adult offspring (Bessa et al., 2019) , confirming the engagement of the ACE2 axis in pregnancy. Gonadotropin stimulation increases the expression of angiotensin-(1--7) and MAS receptor in the rat ovary Angiotensin-(1-7), its receptor Mas, and the angiotensin-converting enzyme type 2 are expressed in the human ovary Increasing Host Cellular Receptor-Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection

abstract:
  The 2019 novel coronavirus (2019-nCoV) appeared in December 2019 and then spread throughout the world rapidly. The virus invades the target cell by binding to angiotensin-converting enzyme (ACE) 2 and modulates the expression of ACE2 in host cells. ACE2, a pivotal component of the renin-angiotensin system, exerts its physiological functions by modulating the levels of angiotensin II (Ang II) and Ang-(1-7). We reviewed the literature that reported the distribution and function of ACE2 in the female reproductive system, hoping to clarify the potential harm of 2019-nCoV to female fertility. The available evidence suggests that ACE2 is widely expressed in the ovary, uterus, vagina and placenta. Therefore, we believe that apart from droplets and contact transmission, the possibility of mother-to-child and sexual transmission also exists. Ang II, ACE2 and Ang-(1-7) regulate follicle development and ovulation, modulate luteal angiogenesis and degeneration, and also influence the regular changes in endometrial tissue and embryo development. Taking these functions into account, 2019-nCoV may disturb the female reproductive functions through regulating ACE2.


id: cord-274259-voyzq05n
author: De Mello, Walmor C.
date: 2014-06-16
txt: ./txt/cord-274259-voyzq05n.txt
cache: ./cache/cord-274259-voyzq05n.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.peptides.2014.06.003
doi: 10.1016/j.peptides.2014.06.003
summary:
  The expression and the role of renin angiotensin aldosterone system (RAAS) components on regulation of cell volume and water transport on vertebrates and invertebrates were reviewed. Evidence is available that in mammals, there are local renin angiotensin systems in different organs including the heart, kidney and possibly in the brain in which RAAS components have been identified intracellularly (see 7, 11, 13, 10, 40 volume and water transport is an old event preserved throughout evolution. In mammalians, components of the renin angiotensin system have been detected in several tissues including the heart, adrenal gland, kidney and in the brain [9, 12, 19, 27, 37, 40] and many of the old properties of RAAS components as regulators of cell volume and water transport seen in invertebrates, are present in the mammalians.

title:
  Regulation of cell volume and water transport – An old fundamental role of the renin angiotensin aldosterone system components at the cellular level

abstract:
  The expression and the role of renin angiotensin aldosterone system (RAAS) components on regulation of cell volume and water transport on vertebrates and invertebrates were reviewed. The presence of these components even in simple organisms like leeches and their relevance for the control of cellular volume and water transport supports the view that the expression of these components, at cellular level, is an acquisition which was preserved throughout evolution.


id: cord-275676-fsumpj4n
author: Kintscher, Ulrich
date: 2020-09-08
txt: ./txt/cord-275676-fsumpj4n.txt
cache: ./cache/cord-275676-fsumpj4n.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32851897/
doi: 10.1161/hypertensionaha.120.15841
abstract: nan
summary:
  title: Plasma Angiotensin Peptide Profiling and ACE (Angiotensin-Converting Enzyme)-2 Activity in COVID-19 Patients Treated With Pharmacological Blockers of the Renin-Angiotensin System P harmacological blockade of the renin-angiotensin system (RAS) with ACE (angiotensin-converting enzyme) inhibitors or angiotensin type 1 receptor blockers (ARB) reduces morbidity and mortality in various cardiovascular diseases. Ang-peptide equilibrium concentrations did not significantly differ between the CTRL and COVID groups without ACE inhibitor/ARB treatment (Figure [B] , left). Ang I+II is a reliable marker for plasma renin activity and did not change significantly, despite the use of ACE inhibitor/ ARB, while median values were clearly increased in patients on ACE inhibitor/ARB. 4 As expected, patients in the CTRL-ACE inhibitor and COVID-ACE inhibitor group showed increased Ang I and markedly suppressed Ang II levels (Figure [B] ), resulting in a significant reduction of the Ang II/Ang I ratio (Figure [C] , lower left).

title:
  Plasma Angiotensin Peptide Profiling and ACE (Angiotensin-Converting Enzyme)-2 Activity in COVID-19 Patients Treated With Pharmacological Blockers of the Renin-Angiotensin System


id: cord-276192-sgts963l
author: Simões e Silva, Ana Cristina
date: 2020-09-29
txt: ./txt/cord-276192-sgts963l.txt
cache: ./cache/cord-276192-sgts963l.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s00467-020-04759-1
doi: 10.1007/s00467-020-04759-1
summary:
  The alternative axis, however, is activated mostly due to Ang-(1-7) binding to Mas receptors, promoting counter-regulatory actions, including decrease of SNS tone, of blood pressure, and of cardiac hypertrophy; increase of baroreflex sensitivity, of NO release, and of natriuresis; and stimulation of vasodilatation. Once activated, the ACE/Ang II/AT1R axis triggers many systemic and local actions which include (1) increased aldosterone production, (2) stimulation of anti-diuretic hormone (ADH) production [31] , (3) activation of sympathetic nervous system (SNS) tone, (4) elevation of BP (5) vasoconstriction, (6) cardiac hypertrophy, (7) fibrosis, (8) inflammation, (9) vascular smooth muscle cell (VSMC) dedifferentiation, (10) reactive oxygen species (ROS) production [32] , and (11) tissue injury. In inflammatory diseases, including arthritis, acute lung injury, asthma, and diabetic nephropathy, several studies have concluded that (1) Ang-(1-7) reduced leukocyte recruitment and the production and expression of chemokines, cytokines, and adhesion molecules and (2) the Mas receptor increased neutrophil apoptosis and stimulated the alternative macrophage activation [12] .

title:
  2020 update on the renin–angiotensin–aldosterone system in pediatric kidney disease and its interactions with coronavirus

abstract:
  The last decade was crucial for our understanding of the renin–angiotensin–aldosterone system (RAAS) as a two-axis, counter-regulatory system, divided into the classical axis, formed by angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the angiotensin type 1 receptor (AT1R), and the alternative axis comprising angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) (Ang-(1-7)), and the Mas receptor. Breakthrough discoveries also took place, with other RAAS endopeptides being described, including alamandine and angiotensin A. In this review, we characterize the two RAAS axes and the role of their components in pediatric kidney diseases, including childhood hypertension (HTN), pediatric glomerular diseases, congenital abnormalities of the kidney and urinary tract (CAKUT), and chronic kidney disease (CKD). We also present recent findings on potential interactions between the novel coronavirus, SARS-CoV-2, and components of the RAAS, as well as potential implications of coronavirus disease 2019 (COVID-19) for pediatric kidney diseases.


id: cord-277669-uujny2dm
author: Lumpuy-Castillo, Jairo
date: 2020-09-04
txt: ./txt/cord-277669-uujny2dm.txt
cache: ./cache/cord-277669-uujny2dm.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32899833/
doi: 10.3390/ijms21186471
summary:
  Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can differentially infect multiple tissues (i.e., lung, vessel, heart, liver) in different stages of disease, and in an ageand sex-dependent manner. In particular, treatments with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) may help to reduce hyperinflammation and viral propagation, while infusion of soluble ACE2 may trap plasma viral particles and increase cardioprotective Ang-(1–9) and Ang-(1–7) peptides. SARS-CoV-2 infection initiates in the respiratory system, when the S protein of its external layer binds the angiotensin-converting enzyme-2 (ACE2) at the plasma membrane of host cells [5] . It was originally suggested that elevation of ACE2 might favor SARS-CoV-2 infection and replication in COVID-19 patients with underlying CV disease and ACEi/ARB treatment [92] . It was originally suggested that elevation of ACE2 might favor SARS-CoV-2 infection and replication in COVID-19 patients with underlying CV disease and ACEi/ARB treatment [92] .

title:
  Cardiovascular Damage in COVID-19: Therapeutic Approaches Targeting the Renin-Angiotensin-Aldosterone System

abstract:
  Coronavirus disease 2019 (COVID-19) is usually more severe and associated with worst outcomes in individuals with pre-existing cardiovascular pathologies, including hypertension or atherothrombosis. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can differentially infect multiple tissues (i.e., lung, vessel, heart, liver) in different stages of disease, and in an age- and sex-dependent manner. In particular, cardiovascular (CV) cells (e.g., endothelial cells, cardiomyocytes) could be directly infected and indirectly disturbed by systemic alterations, leading to hyperinflammatory, apoptotic, thrombotic, and vasoconstrictive responses. Until now, hundreds of clinical trials are testing antivirals and immunomodulators to decrease SARS-CoV-2 infection or related systemic anomalies. However, new therapies targeting the CV system might reduce the severity and lethality of disease. In this line, activation of the non-canonical pathway of the renin-angiotensin-aldosterone system (RAAS) could improve CV homeostasis under COVID-19. In particular, treatments with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) may help to reduce hyperinflammation and viral propagation, while infusion of soluble ACE2 may trap plasma viral particles and increase cardioprotective Ang-(1–9) and Ang-(1–7) peptides. The association of specific ACE2 polymorphisms with increased susceptibility of infection and related CV pathologies suggests potential genetic therapies. Moreover, specific agonists of Ang-(1–7) receptor could counter-regulate the hypertensive, hyperinflammatory, and hypercoagulable responses. Interestingly, sex hormones could also regulate all these RAAS components. Therefore, while waiting for an efficient vaccine, we suggest further investigations on the non-canonical RAAS pathway to reduce cardiovascular damage and mortality in COVID-19 patients.


id: cord-277766-rxmpi61o
author: Guang, Cuie
date: 2012-06-15
txt: ./txt/cord-277766-rxmpi61o.txt
cache: ./cache/cord-277766-rxmpi61o.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S1875213612000952
doi: 10.1016/j.acvd.2012.02.010
summary:
  In a classical RAS, the substrate angiotensinogen (AGT), which is released into the circulation from the liver, is degraded by the enzyme renin that originates in the kidney, generating the inactive angiotensin I (Ang I). The initial drug development of clinical ACE inhibitors was based on the assumption of an active site related to that of carboxypeptidase A but organized to remove a dipeptide rather than a single amino acid from the Cterminus of its substrate. The protective role of XNT against hypertension-induced cardiac fibrosis is associated with activation of ACE2, increases in Ang-(1-7) and inhibition of extracellular signal-regulated kinases [83] . The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate of the N-terminal active site of human angiotensinconverting enzyme The N-terminal active centre of human angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide Angiotensin-converting enzyme 2 activation protects against hypertension-induced cardiac fibrosis involving extracellular signal-regulated kinases

title:
  Three key proteases – angiotensin-I-converting enzyme (ACE), ACE2 and renin – within and beyond the renin-angiotensin system

abstract:
  The discovery of angiotensin-I-converting enzyme 2 (ACE2) and a (pro)renin receptor has renewed interest in the physiology of the renin-angiotensin system (RAS). Through the ACE2/angiotensin-(1–7)/Mas counter-regulatory axis, ACE2 balances the vasoconstrictive, proliferative, fibrotic and proinflammatory effects of the ACE/angiotensin II/AT1 axis. The (pro)renin receptor system shows an angiotensin-dependent function related to increased generation of angiotensin I, and an angiotensin-independent aspect related to intracellular signalling. Activation of ACE2 and inhibition of ACE and renin have been at the core of the RAS regulation. The aim of this review is to discuss the biochemistry and biological functions of ACE, ACE2 and renin within and beyond the RAS, and thus provide a perspective for future bioactives from natural plant and/or food resources related to the three proteases.


id: cord-278265-hgggkr5y
author: Hisatake, Shinji
date: 2020-06-15
txt: ./txt/cord-278265-hgggkr5y.txt
cache: ./cache/cord-278265-hgggkr5y.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32458985/
doi: 10.1042/bsr20192701
summary:
  No previous study has reported serial changes in ACE2 and Ang-(1-7) concentrations after optimal therapy (OT) in acute heart failure (AHF) patients. Results: In the acute phase, Ang-(1-7) and ACE2 concentrations was statistically significantly lower and higher in AHF patients than the healthy individuals (2.40 ± 1.11 vs. We previously reported that acute heart failure (AHF) patients requiring hospitalization had higher serum ACE2 and lower Ang-(1-7) concentrations in the acute phase when compared with the concentrations in healthy volunteers [13] . The present study aimed to investigate the serial changes in the serum ACE2 and Ang-(1-7) concentrations after OT in AHF patients requiring inpatient care. The primary end points of the present study were the serum Ang-(1-7) and ACE2 concentrations at 1 and 3 months later after OT in the patients were compared with the healthy individuals. At 3 months after OT, the statistically significant difference in the serum Ang-(1-7) concentration between heart failure patients and the healthy individuals disappeared.

title:
  The serum angiotensin-converting enzyme 2 and angiotensin-(1-7) concentrations after optimal therapy for acute decompensated heart failure with reduced ejection fraction

abstract:
  Objective: Elucidation of the role of angiotensin-converting enzyme (ACE) 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor axis in heart failure is necessary. No previous study has reported serial changes in ACE2 and Ang-(1-7) concentrations after optimal therapy (OT) in acute heart failure (AHF) patients. We aimed to investigate serial changes in serum ACE2 and Ang-(1-7) concentrations after OT in AHF patients with reduced ejection fraction (EF). Methods: ACE2 and Ang-(1-7) concentrations were measured in 68 AHF patients with reduced EF immediately after admission and 1 and 3 months after OT. These parameters were compared with the healthy individuals at three time points. Results: In the acute phase, Ang-(1-7) and ACE2 concentrations was statistically significantly lower and higher in AHF patients than the healthy individuals (2.40 ± 1.11 vs. 3.1 ± 1.1 ng/ml, P<0.005 and 7.45 ± 3.13 vs. 4.84 ± 2.25 ng/ml, P<0.005), respectively. At 1 month after OT, Ang-(1-7) concentration remained lower in AHF patients than the healthy individuals (2.37 ± 1.63 vs. 3.1 ± 1.1 ng/ml, P<0.05); however, there was no statistically significant difference in ACE2 concentration between AHF patients and the healthy individuals. At 3 months after OT, there were no statistically significant differences in Ang-(1-7) and ACE2 concentrations between AHF patients and the healthy individuals. Conclusion: ACE2 concentration was equivalent between AHF patients and the healthy individuals at 1 and 3 months after OT, and Ang-(1-7) concentration was equivalent at 3 months after OT.


id: cord-287207-z6ddajd6
author: Shenoy, Vinayak
date: 2015-04-24
txt: ./txt/cord-287207-z6ddajd6.txt
cache: ./cache/cord-287207-z6ddajd6.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/B9780128013649000389
doi: 10.1016/b978-0-12-801364-9.00038-9
summary:
  Evidence for this stems from the following observations: (a) PAH and PF are associated with higher circulating levels of angiotensin II (Ang II) 1,2 ; (b) increased concentrations of angiotensinogen (the precursor for Ang II peptide) and angiotensin-converting enzyme (ACE), the major generator of Ang II, have been observed in the lungs of fibrotic and pulmonary hypertensive subjects 3, 4 ; (c) patients carrying the ACE ID/DD genotype, which confers increased ACE levels, are susceptible to COPD and ARDS 5, 6 ; (d) human lung fibroblasts obtained from patients with PF, but not from normal lungs, generate Ang II, 2 suggesting a causative role for this peptide in disease pathogenesis; (e) Ang II induces apoptosis of the alveolar epithelial cells, a key initiating factor for lung fibrogenesis 7 ; (f) Ang II is a potent pulmonary vasoconstrictor with mitogenic properties, that produces migratory, hypertrophic, and proliferative effects on the lung smooth muscles to cause PAH 8 ; (g) Ang II mediates oxidative stress and cytokine signaling, 9 factors that contribute to the pathophysiology of lung diseases; and (h) pharmacological blockade of the RAS using ACE inhibitors (ACEi) or angiotensin receptor blockers (ARB) offers protection against animal models of COPD, PAH, and lung fibrosis.

title:
  Angiotensin-Converting Enzyme 2/Angiotensin-(1-7)/Mas Receptor Axis: Emerging Pharmacological Target for Pulmonary Diseases

abstract:
  Experimental and clinical evidence supports an active role of the renin–angiotensin system (RAS) in the pathogenesis and progression of lung diseases. Angiotensin II (Ang II), a key vasoactive peptide of the RAS, has been implicated in pulmonary disorders such as pulmonary arterial hypertension, lung fibrosis, chronic obstructive pulmonary disease, and acute respiratory distress syndrome. Over the past few years, the classical concept of the RAS has undergone substantial changes to include several new active components. Among them, the identification of angiotensin-converting enzyme 2 (ACE2), its metabolic product angiotensin-(1-7) (Ang-(1-7)), and the Mas receptor has been of biological significance since these components form a counterregulatory axis (ACE2/Ang-(1-7)/Mas) that opposes the detrimental actions of Ang II. In this chapter, we will discuss the role of the ACE2/Ang-(1-7)/Mas axis in lung diseases and describe novel therapeutic approaches to activate this axis for the treatment of pulmonary disorders.


id: cord-291137-09a3tblt
title: Angiotensin II for the Treatment of COVID-19–Related Vasodilatory Shock
author: Chow, Jonathan H.
date: 2020-04-20
txt: ./txt/cord-291137-09a3tblt.txt
cache: ./cache/cord-291137-09a3tblt.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32209811/
doi: 10.1213/ane.0000000000004825
abstract: nan
summary:
  ; Ang-1 = angiotensin I; Ang-2 = angiotensin II; APACHE = Acute Physiology and Chronic Health Evaluation; ARDS = acute respiratory distress syndrome; AT 1 = angiotensin type 1; AT 2 = angiotensin type 2; ATHOS-3 = Angiotensin II for the Treatment of High Output Shock; CI = confidence interval; COVID-19 = coronavirus disease 2019; ECMO = extracorporeal membrane oxygenation; EDHF = endotheliumderived hyperpolarizing factor; ICU = intensive care unit; MAS = mitochondrial assembly protein; NO = nitric oxide; RAAS = renin-angiotensin-aldosterone system; RRT = renal replacement therapy; SARS = severe acute respiratory syndrome C oronavirus disease 2019 (COVID-19) first appeared in Wuhan, China, in early December 2019. 1 In the subgroup of patients admitted to the intensive care unit (ICU), required mechanical ventilation, or died from the disease, 11.9% required continuous renal replacement therapy (RRT), 13.4% developed septic shock, and 40.3% developed acute respiratory distress syndrome (ARDS).


id: cord-291146-f3e5ynhu
author: Sarangarajan, Rangaprasad
date: 2020-09-08
txt: ./txt/cord-291146-f3e5ynhu.txt
cache: ./cache/cord-291146-f3e5ynhu.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32901433/
doi: 10.1007/s40615-020-00853-0
summary:
  The specificity of hypertension and cardiovascular disease as underlying causes for severity of COVID-19 infection, the inherent role of ACE-mediated generation of Ang-II and downstream signalling to potentially exacerbate inflammation and organ damage along with genotypic impact on ACE status provide compelling support of the use of ACE-I and ARBs in the clinical management of patient with positive diagnosis of COVID-19. The significant genetic, scientific and clinical data supporting a potential role for increased ACE levels and associated Ang-II effect in target organs provides compelling argument for use of ACE-I and ARBs in the clinical management of patients with COVID-19 infections to improve outcomes. In summary, this study describes the biological relevance of genetic polymorphism of ACE deletion with higher prevalence in certain ethnic populations including African Americans in context of COVID-19 infection and rationale for the use of ACE-I/ARBs for therapeutic management of severity of morbidity and improving outcomes associated with COVID-19.

title:
  Ethnic Prevalence of Angiotensin-Converting Enzyme Deletion (D) Polymorphism and COVID-19 Risk: Rationale for Use of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers

abstract:
  RATIONALE: Hypertension, obesity and diabetes are major risk factors associated with morbidities underlying COVID-19 infections. Regression analysis correlated presence of ACE insertion/deletion (I/D) polymorphism to COVID-19 incidence and mortality. Furthermore, COVID-19 prevalence correlated to allele frequency of angiotensin-converting enzyme (ACE) deletion (D) polymorphism within the European population. OBJECTIVE: Homozygous ACE deletion polymorphism is associated with increase in ACE and angiotensin II (Ang-II), sustained levels can result in inflammation, fibrosis and organ damage. The ACE DD polymorphism is also associated with hypertension, acute respiratory distress and diabetic nephropathy, all considered high risk for COVID-19 infection and outcomes. The study objective was to describe a biological framework associating ethnic prevalence of ACE deletion polymorphism to COVID-19 comorbidities providing rationale for therapeutic utility of ACE-I/ARBs to improve outcomes. METHOD AND RESULTS: The Allele Frequency Database (ALFRED) was queried for frequency of rs4646994 representing ACE I/D polymorphism. In a total of 349 worldwide population samples, frequency of ACE D allele was higher in European, Asian, and Africans cohorts. In the USA, the frequency of ACE D allele was higher in non-Hispanic Black compared with non-Hispanic White and Mexican Americans. CONCLUSION: COVID-19 binding mediated reduction/inactivation of ACE-II can increase ACE/Ang-II signalling pathway and related pathologies. The presence of ACE DD polymorphism with COVID-19 infection likely augments ACE/Ang-II activities, increasing severity of COVID-19 morbidities and impacts outcomes. Thus, ethnic prevalence of ACE DD polymorphism can explain in part the severity of COVID-19 morbidity providing rationale for the use of ACE-I/ARBs to improve outcomes.


id: cord-291595-8241pjpe
title: COVID-19 cytokine storm: The anger of inflammation
author: Mahmudpour, Mehdi
date: 2020-05-30
txt: ./txt/cord-291595-8241pjpe.txt
cache: ./cache/cord-291595-8241pjpe.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S1043466620301678
doi: 10.1016/j.cyto.2020.155151
summary:
  The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. Because Ang-(1-7) exerts a critical role in counteracting the pro-inflammatory effect of RAAS, protecting from endothelial cell activation and resulting lung damage from inflammatory mediators in the cytokine storm, the administration of Ang-(1-7) or one of its similar agents to patients with COVID-19 pneumonitis has been suggested [35, 66] . We suggested ACE2/Bradykinin/DABK may be involved in the inflammatory response of SARS CoV-2; therefore, blockade of this axis by inhibiting BKB1R may ameliorate a part of the cytokine storm which occurs in COVID-19 infection.

abstract:
  Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.


id: cord-297178-moxhk2e0
author: Novaes Rocha, Vinicius
date: 2020-10-01
txt: ./txt/cord-297178-moxhk2e0.txt
cache: ./cache/cord-297178-moxhk2e0.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0306987720320818?v=s5
doi: 10.1016/j.mehy.2020.110330
summary:
  Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus disease 2019 (COVID-19) is provoking devastating consequences on economic and social fields throughout all continents. Amongst the components of rennin-angiotensin system (RAS), the angiotensin-converting enzyme 2 (ACE2) has gained great prominence for being directly associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the coronavirus related to COVID-19 [4, 5] . ACE2 is a fundamental piece in the pathophysiology of COVID-19, since the high replication capacity of SAR-CoV-2 is directly related to the coupling to ACE2 and cell infection. The ACE2 level reduction caused by SARS-CoV-2 infection may be directly related to the pathogenesis of COVID-19 [26] . The reduction in ACE2 expression may be related to pulmonary inflammation and subsequent cytokine storm seen in patients with severe COVID-19. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severeacute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensinconverting enzyme-2 (ACE2)

title:
  Viral replication of SARS-CoV-2 could be self-limitative - the role of the renin-angiotensin system on COVID-19 pathophysiology

abstract:
  Currently, the world is suffering with one of the biggest pandemics of recent history. Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus disease 2019 (COVID-19) is provoking devastating consequences on economic and social fields throughout all continents. Therefore, pathophysiological knowledge about COVID-19 is imperative for better planning of preventive measures, diagnosis, and therapeutics of the disease. Based on previous studies, this work proposes new hypothesis related to the role of the renin-angiotensin system on the pathophysiology of COVID-19, and its purpose is to enrich the discussion and to offer alternative ways for experimental and clinical studies aiming at the formulation of new diagnosis and / or treatment methods.


id: cord-298490-p1msabl5
author: Obukhov, Alexander G.
date: 2020-07-15
txt: ./txt/cord-298490-p1msabl5.txt
cache: ./cache/cord-298490-p1msabl5.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.2337/dbi20-0019
doi: 10.2337/dbi20-0019
summary:
  As suggested by the recent reports regarding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), upon entry into the host, this virus binds to the extracellular domain of ACE2 in nasal, lung, and gut epithelial cells through its spike glycoprotein subunit S1. In this Perspective, we bring attention to specific factors that may complicate COVID-19 in individuals with diabetes including 1) the presence of bone marrow changes (myeloidosis) that predispose those with diabetes to an excessive proinflammatory response (cytokine storm) and contribute to insulin resistance and reduced vascular repair, and worsening function of the heart, kidney, and systemic vasculature as a whole; 2) increased circulating furin levels that could cleave the spike protein and increase infectivity of SARS-CoV-2; 3) dysregulated autophagy that may promote replication and/or reduce viral clearance; and 4) gut dysbiosis that leads to widespread systemic inflammation, increased gut glucose and sodium absorption, and reduced tryptophan and other key amino acid absorption needed for incretin secretion and glucose homeostasis.

title:
  SARS-CoV-2 Infections and ACE2: Clinical Outcomes Linked With Increased Morbidity and Mortality in Individuals With Diabetes

abstract:
  Individuals with diabetes suffering from coronavirus disease 2019 (COVID-19) exhibit increased morbidity and mortality compared with individuals without diabetes. In this Perspective, we critically evaluate and argue that this is due to a dysregulated renin-angiotensin system (RAS). Previously, we have shown that loss of angiotensin-I converting enzyme 2 (ACE2) promotes the ACE/angiotensin-II (Ang-II)/angiotensin type 1 receptor (AT1R) axis, a deleterious arm of RAS, unleashing its detrimental effects in diabetes. As suggested by the recent reports regarding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), upon entry into the host, this virus binds to the extracellular domain of ACE2 in nasal, lung, and gut epithelial cells through its spike glycoprotein subunit S1. We put forth the hypothesis that during this process, reduced ACE2 could result in clinical deterioration in COVID-19 patients with diabetes via aggravating Ang-II–dependent pathways and partly driving not only lung but also bone marrow and gastrointestinal pathology. In addition to systemic RAS, the pathophysiological response of the local RAS within the intestinal epithelium involves mechanisms distinct from that of RAS in the lung; however, both lung and gut are impacted by diabetes-induced bone marrow dysfunction. Careful targeting of the systemic and tissue RAS may optimize clinical outcomes in subjects with diabetes infected with SARS-CoV-2.


id: cord-299960-ounktxxv
title: New angiotensins
author: Varagic, Jasmina
date: 2008-04-25
txt: ./txt/cord-299960-ounktxxv.txt
cache: ./cache/cord-299960-ounktxxv.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/18437333/
doi: 10.1007/s00109-008-0340-4
summary:
  Interestingly, the spectrum of novel peptides within RAS continues to expand showing that a peptide containing two amino acids more than Ang I, the dodecapeptide angiotensin(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) [Ang(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) ; rat sequence: Asp 1 -Arg 2 -Val 3 -Tyr 4 -Ile 5 -His 6 -Pro 7 -Phe 8 -His 9 -Leu 10 -Leu 11 -Tyr 12 ], could also be a key player in the regulation of cardiovascular function. Together with evidence for increased ACE2 expression in failing human [21] and rat [22] hearts, our study suggests a preserved compensatory response of injured hearts to maintain Ang-(1-7) levels even in the advanced stage of the disease, although it was obviously not sufficient to counteract the deleterious effects of Ang II. Collectively, these data provide strong evidence that Ang-(1-12) may be an alternate precursor substrate for the formation of bioactive angiotensin peptides in the heart, kidney, and circulation that may depend on the localization of one of its processing enzymes, ACE, but not renin.

abstract:
  Accumulation of a large body of evidence during the past two decades testifies to the complexity of the renin–angiotensin system (RAS). The incorporation of novel enzymatic pathways, resulting peptides, and their corresponding receptors into the biochemical cascade of the RAS provides a better understanding of its role in the regulation of cardiovascular and renal function. Hence, in recent years, it became apparent that the balance between the two opposing effector peptides, angiotensin II and angiotensin-(1-7), may have a pivotal role in determining different cardiovascular pathophysiologies. Furthermore, our recent studies provide evidence for the functional relevance of a newly discovered rat peptide, containing two additional amino acid residues compared to angiotensin I, first defined as proangiotensin-12 [angiotensin-(1-12)]. This review focuses on angiotensin-(1-7) and its important contribution to cardiovascular function and growth, while introducing angiotensin-(1-12) as a potential novel angiotensin precursor.


id: cord-303394-iqepytyd
author: Han, Su-Xia
date: 2010-05-15
txt: ./txt/cord-303394-iqepytyd.txt
cache: ./cache/cord-303394-iqepytyd.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.taap.2010.02.009
doi: 10.1016/j.taap.2010.02.009
summary:
  title: Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: Possible involvement of angiotensin-converting enzyme-2 Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along with increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. These results were consistent with our findings in the in vivo study that losartan treatment may attenuate chronic smoking-induced pulmonary artery remodeling and ACE2 reduction in rat lungs. In our present study, we found that ACE2 protein expression was significantly decreased in the lung along with apparent pulmonary arterial remodeling and PAH in the 6-month smoke-exposed rats.

title:
  Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: Possible involvement of angiotensin-converting enzyme-2

abstract:
  Chronic cigarette smoking induces pulmonary arterial hypertension (PAH) by largely unknown mechanisms. Renin–angiotensin system (RAS) is known to function in the development of PAH. Losartan, a specific angiotensin II receptor antagonist, is a well-known antihypertensive drug with a potential role in regulating angiotensin-converting enzyme-2 (ACE2), a recently found regulator of RAS. To determine the effect of losartan on smoke-induced PAH and its possible mechanism, rats were daily exposed to cigarette smoke for 6 months in the absence and in the presence of losartan. Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along with increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Losartan administration ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs. In cultured primary pulmonary artery smooth muscle cells (PASMCs) from 3- and 6-month smoke-exposed rats, ACE2 levels were significantly lower than in those from the control rats. Moreover, PASMCs from 6-month exposed rats proliferated more rapidly than those from 3-month exposed or control rats, and cells grew even more rapidly in the presence of DX600, an ACE2 inhibitor. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. Our study might provide insight into the development of new therapeutic interventions for PAH smokers.


id: cord-304976-egbl3ljp
title: Neuronal Angiotensin
author: Allen, A.M.
date: 2008-11-05
txt: ./txt/cord-304976-egbl3ljp.txt
cache: ./cache/cord-304976-egbl3ljp.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/B9780080450469020532
doi: 10.1016/b978-008045046-9.02053-2
summary:
  Within the brain renin, some questions remain as to how the precursor, angiotensinogen, and its processing enzymes interact to produce the active compounds, angiotensin II/III, because they are rarely localized to the same brain nucleus let alone the same cell. Further work throughout the 1900s defined a humoral system in which the active agent, angiotensin (Ang II), was derived from a protein precursor, angiotensinogen (Aogen), via the sequential action of two enzymes, renin and angiotensin converting enzyme (ACE) (Figure 1 ). It has since been demonstrated that many tissues, including kidney, heart, blood vessels, adrenal gland, uterus, testes, and brain, have the potential to produce Ang independently of the circulating renin-angiotensin system. Some of the most convincing evidence for the existence of a brain renin-angiotensin system is derived from examination of the distribution of the Ang receptors and the physiological actions exerted through them.

abstract:
  Many tissues, including the brain, contain all components of the renin–angiotensin system and generate angiotensin peptides independent of the systemic, circulating system. Within the brain renin, some questions remain as to how the precursor, angiotensinogen, and its processing enzymes interact to produce the active compounds, angiotensin II/III, because they are rarely localized to the same brain nucleus let alone the same cell. These questions aside, there is clear evidence for actions of angiotensin peptides in regions behind the blood–brain barrier. Receptors for angiotensin peptides, including AT(1) and AT(2) receptors, are distributed in a characteristic pattern throughout the brain, with many of these sites behind the blood–brain barrier. Stimulation of these receptors affects multiple physiological functions – actions which often complement the physiological roles established for the systemic renin–angiotensin system. These include effects on fluid and electrolyte homeostasis, autonomic and neuroendocrine regulation, and modulation of sensory function. Moreover, administration of selective receptor antagonists attenuates several of these functions when they are activated in response to physiological stimuli, such as dehydration. Together, these observations point to important roles for brain-derived angiotensin peptides in a wide range of physiological functions.


id: cord-307894-pfsztifl
title: Chapter 100 Angiotensin-Converting Enzyme-2
author: Clarke, Nicola E.
date: 2013-12-31
txt: ./txt/cord-307894-pfsztifl.txt
cache: ./cache/cord-307894-pfsztifl.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/B9780123822192001009
doi: 10.1016/b978-0-12-382219-2.00100-9
summary:
  Keywords: Angiotensin, angiotensin-converting enzyme 2 (ACE2), apelin, bradykinin, carboxypeptidase, cardiovascular, collectrin, renin-angiotensin system, SARS virus, shedding, transmembrane, vasoactive, zinc-binding motif. Despite high similarity in sequence to ACE, particularly around the active site, ACE2 functions as a carboxypeptidase, rather than a peptidyl dipeptidase, cleaving the C-terminal amino acid from susceptible substrates. Key active site residues of ACE2 ( Figure 100 .1) were identified by site-directed mutagenesis based on the structure of the single domain testicular form of ACE [15] . Angiotensin-converting enzyme-2 (ACE2): comparative modeling of the active site, specificity requirements., chloride dependence Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase Substrate-based design of the first class of angiotensin-converting enzyme-related carboxypeptidase (ACE2) inhibitors Residues affecting the chloride regulation and substrate selectivity of the angiotensinconverting enzymes (ACE and ACE2) identified by site-directed mutagenesis Increased angiotensin-(1À7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme Homologue ACE2

abstract:
  The third edition of the Handbook of Proteolytic Enzymes aims to be a comprehensive reference work for the enzymes that cleave proteins and peptides, and contains over 850 chapters. Each chapter is organized into sections describing the name and history, activity and specificity, structural chemistry, preparation, biological aspects, and distinguishing features for a specific peptidase. The subject of Chapter 100 is Angiotensin-Converting Enzyme-2. Keywords: Angiotensin, angiotensin-converting enzyme 2 (ACE2), apelin, bradykinin, carboxypeptidase, cardiovascular, collectrin, renin-angiotensin system, SARS virus, shedding, transmembrane, vasoactive, zinc-binding motif.


id: cord-309619-glb2y82u
title: The four horsemen of a viral Apocalypse: The pathogenesis of SARS-CoV-2 infection (COVID-19)
author: Domingo, Pere
date: 2020-07-29
txt: ./txt/cord-309619-glb2y82u.txt
cache: ./cache/cord-309619-glb2y82u.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.ebiom.2020.102887
doi: 10.1016/j.ebiom.2020.102887
summary:
  Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1–7)/Mas1R axis. SARS-CoV induces the signal transducer and activator of transcription 1 TACE TNF-a converting enzyme TBK1 TANK-binding kinase 1 TLR toll-like receptor TMPRSS2 type II transmembrane serine protease TNF-a tumor necrosis alpha TRAF3 TNF receptor-associated factor 3 XCR1 XCL1 (Chemokine [C motif] ligand 1) and XCL3 (Chemokine [C motif] ligand 3) receptor production of double-membrane vesicles that lack PRRs and can then replicate in these vesicles [18] . COVID-19 patients have high serum levels of inflammatory cytokines, including interleukin (IL)-2, IL-7, IL-10, granulocyte-colony stimulating factor (G-CSF), interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage SARS-CoV-2 infects primarily type II pneumocytes through binding to the ACE2 receptor. ACE2 = Angiotensin-converting enzyme 2; SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2; Ang II = Angiotensin II; ROS = Reactive oxygen species; AT1R = Angiotensin 1 receptor; ADAM17 = A disintegrin and metalloproteinase domain 17; TNF-a = Tumor necrosis factor alpha; TMPRSS2 = transmembrane protease serine 2.

abstract:
  The pathogenesis of coronavirus disease 2019 (COVID-19) may be envisaged as the dynamic interaction between four vicious feedback loops chained or happening at once. These are the viral loop, the hyperinflammatory loop, the non-canonical renin-angiotensin system (RAS) axis loop, and the hypercoagulation loop. Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1–7)/Mas1R axis. The viral feedback loop includes evading the host's innate response, uncontrolled viral replication, and turning on a hyperactive adaptative immune response. The inflammatory loop is composed of the exuberant inflammatory response feeding back until exploding in an actual cytokine storm. Downregulation of the ACE2/Ang-(1–7)/Mas1R axis leaves the lung without a critical defense mechanism and turns the scale to the inflammatory side of the RAS. The coagulation loop is a hypercoagulable state caused by the interplay between inflammation and coagulation in an endless feedback loop. The result is a hyperinflammatory and hypercoagulable state producing acute immune-mediated lung injury and eventually, adult respiratory distress syndrome.


id: cord-310124-3bc8zeww
author: Ratajczak, Mariusz Z.
date: 2020-07-20
txt: ./txt/cord-310124-3bc8zeww.txt
cache: ./cache/cord-310124-3bc8zeww.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s12015-020-10010-z
doi: 10.1007/s12015-020-10010-z
summary:
  We demonstrate for the first time that ACE2 and the entry-facilitating transmembrane protease TMPRSS2 are expressed on very small CD133(+)CD34(+)Lin(−)CD45(−) cells in human umbilical cord blood (UCB), which can be specified into functional HSCs and EPCs. The existence of these cells known as very small embryonic-like stem cells (VSELs) has been confirmed by several laboratories, and some of them may correspond to putative postnatal hemangioblasts. Moreover, we demonstrate for the first time that, in human VSELs and HSCs, the interaction of the ACE2 receptor with the SARS-CoV-2 spike protein activates the Nlrp3 inflammasome, which if hyperactivated may lead to cell death by pyroptosis. We sorted very small CD34 + Lin − CD45 − cells (VSELs) and CD34 + Lin − CD45 + cells (HSCs) from UCB by FACS (Fig. 1) and phenotyped them by real-time PCR for expression of mRNAs for the ACE2 entry receptor for SARS-CoV-2, the spike protein-processing enzyme TIMPRSS2, the receptors for Ang II (AT 1 R and AT 2 R), and the Ang (1-7) receptor (MasR, Fig. 2) .

title:
  SARS-CoV-2 Entry Receptor ACE2 Is Expressed on Very Small CD45(−) Precursors of Hematopoietic and Endothelial Cells and in Response to Virus Spike Protein Activates the Nlrp3 Inflammasome

abstract:
  Angiotensin-converting enzyme 2 (ACE2) plays an important role as a member of the renin–angiotensin–aldosterone system (RAAS) in regulating the conversion of angiotensin II (Ang II) into angiotensin (1–7) (Ang [1–7]). But at the same time, while expressed on the surface of human cells, ACE2 is the entry receptor for SARS-CoV-2. Expression of this receptor has been described in several types of cells, including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), which raises a concern that the virus may infect and damage the stem cell compartment. We demonstrate for the first time that ACE2 and the entry-facilitating transmembrane protease TMPRSS2 are expressed on very small CD133(+)CD34(+)Lin(−)CD45(−) cells in human umbilical cord blood (UCB), which can be specified into functional HSCs and EPCs. The existence of these cells known as very small embryonic-like stem cells (VSELs) has been confirmed by several laboratories, and some of them may correspond to putative postnatal hemangioblasts. Moreover, we demonstrate for the first time that, in human VSELs and HSCs, the interaction of the ACE2 receptor with the SARS-CoV-2 spike protein activates the Nlrp3 inflammasome, which if hyperactivated may lead to cell death by pyroptosis. Based on this finding, there is a possibility that human VSELs residing in adult tissues could be damaged by SARS-CoV-2, with remote effects on tissue/organ regeneration. We also report that ACE2 is expressed on the surface of murine bone marrow-derived VSELs and HSCs, although it is known that murine cells are not infected by SARS-CoV-2. Finally, human and murine VSELs express several RAAS genes, which sheds new light on the role of these genes in the specification of early-development stem cells. [Figure: see text]


id: cord-311099-59pnm4fn
title: Liver disease and the renin–angiotensin system: Recent discoveries and clinical implications
author: Lubel, John S
date: 2008-06-28
txt: ./txt/cord-311099-59pnm4fn.txt
cache: ./cache/cord-311099-59pnm4fn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/18557800/
doi: 10.1111/j.1440-1746.2008.05461.x
summary:
  Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang‐(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang‐(1–7) rather than inhibition of Ang II production or receptor binding. 42 A great deal of evidence supporting the role of the RAS in hepatic fibrosis has come from animal studies using ACE inhibitors and angiotensin receptor blockers (ARB). A pilot study examining the effects of 6 months of losartan treatment on liver fibrosis in chronic hepatitis C demonstrated a significant decrease in fibrosis stage in the treated group compared to control patients.

abstract:
  The renin–angiotensin system (RAS) is a key regulator of vascular resistance, sodium and water homeostasis and the response to tissue injury. Historically, angiotensin II (Ang II) was thought to be the primary effector peptide of this system. Ang II is produced predominantly by the effect of angiotensin converting enzyme (ACE) on angiotensin I (Ang I). Ang II acts mainly through the angiotensin II type‐1 receptor (AT(1)) and, together with ACE, these components represent the ‘classical’ axis of the RAS. Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. In 2000, two groups using different methodologies identified a homolog of ACE, called ACE2, which cleaves Ang II to form the biologically active heptapeptide, Ang‐(1–7). Conceptually, ACE2, Ang‐(1–7), and its putative receptor, the mas receptor represent an ‘alternative’ axis of the RAS capable of opposing the often deleterious actions of Ang II. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang‐(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang‐(1–7) rather than inhibition of Ang II production or receptor binding. The present review focuses on the novel components and pathways of the RAS with particular reference to their potential contribution towards the pathophysiology of liver disease.


id: cord-313664-qq0h68vc
title: Renin‐angiotensin system revisited
author: Fyhrquist, F.
date: 2008-08-08
txt: ./txt/cord-313664-qq0h68vc.txt
cache: ./cache/cord-313664-qq0h68vc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/18793332/
doi: 10.1111/j.1365-2796.2008.01981.x
summary:
  The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin‐converting enzyme (ACE). The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. It was not until the discovery of orally effective angiotensin-converting enzyme (ACE) inhibitors, the first of which was captopril [2] , that the paramount importance of RAS in cardiovascular homeostasis and disease was being appreciated. Angiotensin-converting enzyme 2 and Ang 1-7 may play an important role in cardiovascular physiology and pathophysiology, e.g. by modulating or counterbalancing excess activity of the ''classical'' RAS [45, 46] . Angiotensin-converting enzyme inhibitors and ARBs (Fig. 5) are well established corner stones in the prevention and treatment of hypertension and cardiovascular disease, as demonstrated by numerous clinical trials and world wide clinical practice.

abstract:
  New components and functions of the renin‐angiotensin system (RAS) are still being unravelled. The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin‐converting enzyme (ACE). Ang II, still considered the main effector of RAS was believed to act only as a circulating hormone via angiotensin receptors, AT1 and AT2. Since then, an expanded view of RAS has gradually emerged. Local tissue RAS systems have been identified in most organs. Recently, evidence for an intracellular RAS has been reported. The new expanded view of RAS therefore covers both endocrine, paracrine and intracrine functions. Other peptides of RAS have been shown to have biological actions; angiotensin 2–8 heptapeptide (Ang III) has actions similar to those of Ang II. Further, the angiotensin 3–8 hexapeptide (Ang IV) exerts its actions via insulin‐regulated amino peptidase receptors. Finally, angiotensin 1–7 (Ang 1–7) acts via mas receptors. The discovery of another ACE2 was an important complement to this picture. The recent discovery of renin receptors has made our view of RAS unexpectedly complex and multilayered. The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. Great expectations are now generated by the introduction of renin inhibitors. Indeed, RAS regulates much more and diverse physiological functions than previously believed.


id: cord-314102-8jf3fnqe
title: Advances in research on ACE2 as a receptor for 2019-nCoV
author: Wu, Jie
date: 2020-08-11
txt: ./txt/cord-314102-8jf3fnqe.txt
cache: ./cache/cord-314102-8jf3fnqe.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32780149/
doi: 10.1007/s00018-020-03611-x
summary:
  Although 2019-nCoV and SARS-CoV are very similar viruses genomically and structurally, the huge number of severe cases and deaths now being caused by 2019-nCoV infections has understandably prompted intense research on the receptor used by it to enter human cells. Angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV, now appears likely to mediate 2019-nCoV entry into human cells. Some recent studies have suggested Cellular and Molecular Life Sciences * Xiuhong Yang yangxiuhong@ncst.edu.cn 1 that 2019-nCoV may infect host cells through the ACE2 receptor, as has already been established for SARS-CoV [7] [8] [9] [10] . In this review, the latest advances in our understanding of the roles played by ACE2 in enzyme catalysis, CoV invasion, cellular expression changes after viral-host cell binding, and its relationships with viral transmission and population susceptibility are described in the context of the pathogenesis of COVID-19. Therefore, it is speculated that like SARS-CoV, 2019-nCoV infects host cells via the mediating effects of its S protein and ACE2 receptors on the surfaces of human cells.

abstract:
  Currently, a novel coronavirus (SARS-CoV-2, also called 2019-nCoV) has triggered pandemic Coronavirus Disease 2019 (COVID-19), an acute infectious respiratory disease that first became epidemic in Wuhan (China) and is now spreading worldwide. Although 2019-nCoV and SARS-CoV are very similar viruses genomically and structurally, the huge number of severe cases and deaths now being caused by 2019-nCoV infections has understandably prompted intense research on the receptor used by it to enter human cells. Angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV, now appears likely to mediate 2019-nCoV entry into human cells. In this review, we describe the roles performed by ACE2 as an enzymatic catalyst and as a receptor for this novel coronavirus. We also summarize the latest research pertaining to the changes noted in ACE2 expression after viral binding, and the relationships relating to virus transmission and population susceptibility to it. Lastly, we speculate on the pathogenesis of COVID-19 and provide a useful reference for drug development against this aggressive virus.


id: cord-317472-6ese0c0e
title: ACE and ACE2: a tale of two enzymes
author: Zisman, Lawrence S.
date: 2005-02-01
txt: ./txt/cord-317472-6ese0c0e.txt
cache: ./cache/cord-317472-6ese0c0e.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/15671047/
doi: 10.1093/eurheartj/ehi043
abstract: nan
summary:
  In response to RAAS activation there is an increase, at the level of both gene and protein expression, of components which decrease the local concentration of Ang II and which generate bioactive compounds that counteract Ang II-mediated effects. 5 ACE2 may be important as a counter-regulatory enzyme not only because it decreases local cardiac Ang II concentrations, but also because its product Ang-(1-7) mediates specific effects through its recently identified receptor, the mas oncogene product (MAS). The authors found a marked increase in ACE2 gene expression in the border/infarct zone as well as in viable myocardium in the post-myocardial infarction rat heart. 9 Furthermore, it has been shown that ACE2 gene expression and activity are markedly increased in failing human heart. ACE2 gene expression is up-regulated in the human failing heart Increased angiotensin-(1-7) forming activity in failing human heart ventricles: evidence for upregulation of the angiotensinconverting enzyme homologue


id: cord-317888-ei598viq
title: Antagonizing the renin–angiotensin–aldosterone system in the era of COVID-19
author: Sarzani, Riccardo
date: 2020-05-18
txt: ./txt/cord-317888-ei598viq.txt
cache: ./cache/cord-317888-ei598viq.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s11739-020-02365-5
doi: 10.1007/s11739-020-02365-5
abstract: nan
summary:
  Moreover, ACE2 interacts with another branch of RAAS based on Ang peptides in which the aminoterminal aspartate is replaced by alanine (Alatensins), leading to the production of Ala-Ang 1-7 (Alamandine) that has been found to bind Mas-related G protein-coupled receptor D (MrgD) and may also protect against lung injury and fibrosis, improving vascular/endothelial dysfunction [4] . Same favorable results have been found in a small UK cohort study on 205 patients admitted for COVID-19, in which treatment with ACE-I was associated with a reduced risk of rapidly deteriorating severe disease [pre-print] . In another small sample of COVID-19 patients, ACE-I and ARB therapy affected both IL-6 and peripheral T cell levels and was associated with lower rates of severe disease [6] . Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) infection in Wuhan


id: cord-318327-9sh2eksm
author: Garg, M.
date: 2012-01-05
txt: ./txt/cord-318327-9sh2eksm.txt
cache: ./cache/cord-318327-9sh2eksm.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/22221317/
doi: 10.1111/j.1365-2036.2011.04971.x
summary:
  Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. The contemporary view of the RAS has evolved from that of a simple linear pathway involving the conversion of angiotensinogen to angiotensin II (Ang II) via a two-step process facilitated by renin and angiotensin converting enzyme (ACE), to a much more complex system involving homologues of ACE and multiple angiotensin peptides which play supplementary and counter-regulatory roles ( Figure 1 ). Angiotensin converting enzyme inhibition or angiotensin receptor antagonism have been shown to produce a number of beneficial anti-inflammatory effects in rodent models of intestinal inflammation.

title:
  Review article: the pathophysiological roles of the renin–angiotensin system in the gastrointestinal tract

abstract:
  BACKGROUND: The renin‐angiotensin system (RAS) is a homeostatic pathway widely known to regulate cardiovascular and renal physiology; however, little is known about its influence in gastrointestinal tissues. AIM: To elicit the anatomical distribution and physiological significance of the components of the RAS in the gastrointestinal tract. METHODS: An extensive online literature review including Pubmed and Medline. RESULTS: There is evidence for RAS involvement in gastrointestinal physiology and pathophysiology, with all the components required for autonomous regulation identified throughout the gastrointestinal tract. The RAS is implicated in the regulation of glucose, amino acid, fluid and electrolyte absorption and secretion, motility, inflammation, blood flow and possibly malignant disease within the gastrointestinal tract. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Given the ready availability of drugs that modify the RAS and their excellent safety profile, an opportunity exists for investigation of their possible therapeutic role in a variety of human gastrointestinal diseases. CONCLUSIONS: The gastrointestinal renin‐angiotensin system appears to be intricately involved in a number of physiological processes, and provides a possible target for novel investigative and therapeutic approaches.


id: cord-318358-glbr8kxh
title: COVID-19 and the RAAS
author: Naik, George O A
date: 2020-06-20
txt: ./txt/cord-318358-glbr8kxh.txt
cache: ./cache/cord-318358-glbr8kxh.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1093/cid/ciaa818
doi: 10.1093/cid/ciaa818
abstract: nan
summary:
  Further to Thomas Hanff et al [1] timely call for epidemiological and clinical investigations of COVID-19 infectious disease, measurements of the renin angiotensin aldosterone system (RAAS) components, as sub-studies would be insightful of this pandemic. Angiotensin-converting enzyme 2 (ACE 2) participates in the coronavirus (SARS-CoV-2) cell entry. Drugs that block RAAS also affect ACE 2 expression: it is down regulated by renin inhibition (RI) and up regulated by angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) (1) and mineralocorticoid receptor antagonists (MRAs) [2] . Such perturbations would also indirectly influence other RAAS components, and the coordination between circulating and local tissue expressions, as shown in Figure 1 ACE 2 is distributed throughout the body and is abundantly expressed in the lung, small intestine, and in blood vessels of many organs including the brain, heart, kidney and testis [4] . Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients


id: cord-320331-wtxja5i9
author: Cabbab, Iris Louise N.
date: 2020-10-08
txt: ./txt/cord-320331-wtxja5i9.txt
cache: ./cache/cord-320331-wtxja5i9.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.virusres.2020.198190
doi: 10.1016/j.virusres.2020.198190
summary:
  It is important to note that since the approach of this paper is to provide current knowledge on the anatomic, physiologic and molecular bases of anti-inflammatory drug and corticosteroid action on the RAAS, this paper will not demonstrate a systematic review or meta-analysis of current clinical evidence, but will only provide insight on the probable influences of the discussed pathways on early SARS-CoV-2 infection. A correspondence by Fang et al published at The Lancet this March discussed that hypertensives and diabetics taking ACE2 inhibitor (ACEi) and angiotensin receptor blocking (ARB) drugs may be at an increased risk of infection and severity by SARS-CoV-2 and COVID-19, respectively, citing three studies wherein diabetes and hypertension were major comorbidities of patients with severe COVID-19 and of non-survivors [20] .

title:
  Anti-Inflammatory Drugs and the Renin-Angiotensin-Aldosterone System: Current Knowledge and Potential Effects on Early SARS-CoV-2 Infection

abstract:
  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease 19 (COVID-19), and is genetically related to the 2003 SARS and Middle East respiratory syndrome (MERS-CoV) coronaviruses. Recent studies have reported that similar to SARS-CoV, this strain expresses a spike protein (S) with a receptor binding domain (RBD) that binds to angiotensin-converting enzyme 2 (ACE2) – an enzyme expressed mostly in the endothelium, kidneys, heart, gastrointestinal tract and lungs – to facilitate viral entry and intracellular replication. Incidentally, the renin-angiotensin-aldosterone system (RAAS) is integral to physiologic control of both ACE and ACE2 expression, and is an essential system utilized by SARS-CoV-2, albeit with varying schools of thought on how it can affect viral entry. In this paper, we will review current knowledge on the RAAS and how it can be affected by non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroid use at the organ and cellular levels. We will then discuss the relevance of these interactions on organ-specific ACE2 expression, and provide scientific insights on how this mechanism can potentially affect SARS-CoV-2 infection in the early phases of disease. From the standpoint of other known viruses, we will then aim to discuss the potential uses or restrictions of these drugs in viral infection, and provide an update on relevant studies about COVID-19.


id: cord-322212-8xrehbd1
author: Wang, Hanyin
date: 2020-04-23
txt: ./txt/cord-322212-8xrehbd1.txt
cache: ./cache/cord-322212-8xrehbd1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.chest.2020.04.015
doi: 10.1016/j.chest.2020.04.015
summary:
  title: Unexpected BP Sensitivity to Angiotensin II in a Patient With Coronavirus Disease 2019, ARDS, and Septic Shock We report the case of an 88-year-old man with coronavirus disease 2019 (COVID-19) who presented with ARDS and septic shock. 1 An estimated 5.0% of patients with coronavirus disease 2019 (COVID-19) required ICU admission, 2.3% underwent mechanical ventilation, and 1.1% had septic shock. 2 Angiotensin II (Ang-2) is a synthetic vasopressor that received US Food and Drug Administration approval in 2017 for treatment of refractory vasodilatory shock. We report our experience with Ang-2 for septic shock in a critically ill patient with COVID-19. He became hypotensive and required ABBREVIATIONS: ACE = angiotensin-converting enzyme; ACE2 = angiotensin-converting enzyme 2; Ang-2 = angiotensin II; COVID-19 = coronavirus disease 2019; SARS-CoV = severe acute respiratory syndrome-related coronavirus; SARS-CoV-2 = 2019 novel coronavirus On ICU day 2, the SARS-CoV-2 polymerase chain reaction result was positive.

title:
  Unexpected BP Sensitivity to Angiotensin II in a Patient With Coronavirus Disease 2019, ARDS, and Septic Shock

abstract:
  We report the case of an 88-year-old man with coronavirus disease 2019 (COVID-19) who presented with ARDS and septic shock. The patient had exquisite BP sensitivity to low-dose angiotensin II (Ang-2), allowing for rapid liberation from high-dose vasopressors. We hypothesize that sensitivity to Ang-2 might be related to biological effect of severe acute respiratory syndrome coronavirus 2 infection. The case is suggestive of a potential role for synthetic Ang-2 for patients with COVID-19 and septic shock. Further studies are needed to confirm our observed clinical efficacy.


id: cord-325610-n3zb36am
author: Postlethwait, John H.
date: 2020-09-02
txt: ./txt/cord-325610-n3zb36am.txt
cache: ./cache/cord-325610-n3zb36am.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.09.01.278366
doi: 10.1101/2020.09.01.278366
summary:
  title: An intestinal cell type in zebrafish is the nexus for the SARS-CoV-2 receptor and the Renin-Angiotensin-Aldosterone System that contributes to COVID-19 comorbidities To exploit zebrafish (Danio rerio) as a disease model to understand mechanisms regulating the RAAS and its relationship to COVID-19 comorbidities, we must first identify zebrafish orthologs and co-orthologs of human RAAS genes, and second, understand where and when these genes are expressed in specific cells in zebrafish development. Results further identified a specific intestinal cell type in zebrafish larvae as the site of expression for key RAAS components, including Ace, Ace2, the coronavirus co-receptor Slc6a19, and the Angiotensin-related peptide cleaving enzymes Anpep and Enpep. These results identify specific genes and cell types to exploit zebrafish as a disease model for understanding the mechanisms leading to COVID-19 comorbidities. SUMMARY STATEMENT Genomic analyses identify zebrafish orthologs of the Renin-Angiotensin-Aldosterone System that contribute to COVID-19 comorbidities and single-cell transcriptomics show that they act in a specialized intestinal cell type.

title:
  An intestinal cell type in zebrafish is the nexus for the SARS-CoV-2 receptor and the Renin-Angiotensin-Aldosterone System that contributes to COVID-19 comorbidities

abstract:
  People with underlying conditions, including hypertension, obesity, and diabetes, are especially susceptible to negative outcomes after infection with the coronavirus SARS-CoV-2. These COVID-19 comorbidities are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from rapidly dropping blood pressure or dehydration via the peptide Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II, thus counteracting its chronic effects. Ace2 is also the SARS-CoV-2 receptor. Ace, the coronavirus, and COVID-19 comorbidities all regulate Ace2, but we don’t yet understand how. To exploit zebrafish (Danio rerio) as a disease model to understand mechanisms regulating the RAAS and its relationship to COVID-19 comorbidities, we must first identify zebrafish orthologs and co-orthologs of human RAAS genes, and second, understand where and when these genes are expressed in specific cells in zebrafish development. To achieve these goals, we conducted genomic analyses and investigated single cell transcriptomes. Results showed that most human RAAS genes have an ortholog in zebrafish and some have two or more co-orthologs. Results further identified a specific intestinal cell type in zebrafish larvae as the site of expression for key RAAS components, including Ace, Ace2, the coronavirus co-receptor Slc6a19, and the Angiotensin-related peptide cleaving enzymes Anpep and Enpep. Results also identified specific vascular cell subtypes as expressing Ang II receptors, apelin, and apelin receptor genes. These results identify specific genes and cell types to exploit zebrafish as a disease model for understanding the mechanisms leading to COVID-19 comorbidities. SUMMARY STATEMENT Genomic analyses identify zebrafish orthologs of the Renin-Angiotensin-Aldosterone System that contribute to COVID-19 comorbidities and single-cell transcriptomics show that they act in a specialized intestinal cell type.


id: cord-326223-q6e60nf8
title: Organ-specific distribution of ACE2 mRNA and correlating peptidase activity in rodents
author: Gembardt, Florian
date: 2005-02-16
txt: ./txt/cord-326223-q6e60nf8.txt
cache: ./cache/cord-326223-q6e60nf8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/15949646/
doi: 10.1016/j.peptides.2005.01.009
summary:
  Biochemical analysis revealed that angiotensin-converting enzyme related carboxy-peptidase (ACE2) cleaves angiotensin (Ang) II to Ang-(1–7), a heptapeptide identified as an endogenous ligand for the G protein-coupled receptor Mas. No data are currently available that systematically describe ACE2 distribution and activity in rodents. Therefore, we analyzed the ACE2 expression in different tissues of mice and rats on mRNA (RNase protection assay) and protein levels (immunohistochemistry, ACE2 activity, western blot). Although ACE2 mRNA in both investigated species showed the highest expression in the ileum, the mouse organ exceeded rat ACE2, as also demonstrated in the kidney and colon. Using a commercial polyclonal antibody in western blot for the quantification of protein levels in mouse and rat tissues (Fig. 4) a pattern completely different from RNA expression and ACE2 activity was found.

abstract:
  Biochemical analysis revealed that angiotensin-converting enzyme related carboxy-peptidase (ACE2) cleaves angiotensin (Ang) II to Ang-(1–7), a heptapeptide identified as an endogenous ligand for the G protein-coupled receptor Mas. No data are currently available that systematically describe ACE2 distribution and activity in rodents. Therefore, we analyzed the ACE2 expression in different tissues of mice and rats on mRNA (RNase protection assay) and protein levels (immunohistochemistry, ACE2 activity, western blot). Although ACE2 mRNA in both investigated species showed the highest expression in the ileum, the mouse organ exceeded rat ACE2, as also demonstrated in the kidney and colon. Corresponding to mRNA, ACE2 activity was highest in the ileum and mouse kidney but weak in the rat kidney, which was also confirmed by immunohistochemistry. Contrary to mRNA, we found weak activity in the lung of both species. Our data demonstrate a tissue- and species-specific pattern for ACE2 under physiological conditions.


id: cord-326405-3446eyi3
title: Angiotensin-converting enzyme 2: Possible role in hypertension and kidney disease
author: Wysocki, Jan
date: 2008-02-07
txt: ./txt/cord-326405-3446eyi3.txt
cache: ./cache/cord-326405-3446eyi3.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/18367030/
doi: 10.1007/s11906-008-0014-1
summary:
  The high catalytic efficiency of ACE2 for the generation of angiotensin (ANG)-1-7 from ANG II suggests an important role of ACE2 in preventing ANG II accumulation, while at the same time enhancing ANG-1-7 formation. [41] , primarily describing an Ace2 knockout and its associated cardiac pathology, also reported that ACE2 was reduced at the gene and protein level in kidneys from three separate rat models of spontaneous and diet-induced hypertension. Investigating the role of ACE2 in those two prevalent diseases and whether its effects are mediated by ANG II or ANG-(1-7) and other biologically active peptides, which are also substrates of ACE2, opens the way for developing new therapeutic targets in hypertension. ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice Also, pharmacologic ACE2 inhibition was associated with increased albuminuria, suggesting a role of glomerular ACE2 in diabetic kidney injury

abstract:
  The discovery of angiotensin-converting enzyme (ACE) 2 adds a new level of complexity to the understanding of the renin-angiotensin system. The high catalytic efficiency of ACE2 for the generation of angiotensin (ANG)-1-7 from ANG II suggests an important role of ACE2 in preventing ANG II accumulation, while at the same time enhancing ANG-1-7 formation. ACE and ACE2 may have counterbalancing functions and a regulatory role in fine-tuning the rate at which ANG peptides are formed and degraded. By counterregulating the actions of ACE on ANG II formation, ACE2 may play a role in maintaining a balanced status of the renninangiotensin system. This review focuses on the function of ACE2 and its possible roles in kidney disease and hypertension. Studies using models of ACE2 ablation and the pharmacologic administration of an ACE2 inhibitor suggest that decreased ACE2 activity alone or in combination with increased ACE activity may play a role in both diseases.


id: cord-330558-autprmr4
title: ACE2, a new regulator of the renin–angiotensin system
author: Burrell, Louise M.
date: 2004-05-31
txt: ./txt/cord-330558-autprmr4.txt
cache: ./cache/cord-330558-autprmr4.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/15109615/
doi: 10.1016/j.tem.2004.03.001
summary:
  Ang II is thought to be responsible for most of the physiological and pathophysiological effects of the RAS, and inhibitors of ACE that reduce the formation of Ang II have been highly successful in the management of hypertension, are standard therapy following myocardial infarction to delay the development of heart failure, and reduce the rate of progression of renal disease [2, 3] . Recently, however, the classical view of the RAS has been challenged by the discovery of the enzyme ACE2 [4, 5] , in addition to the increasing awareness that many angiotensin peptides other than Ang II have biological activity and physiological importance [6] . Blockade of the RAS with ACE inhibitors or Ang II type 1 receptor antagonists has clearly established its key role in the pathophysiology of an increasing number of diseases, including hypertension, heart failure, ventricular remodelling, renoprotection and diabetic complications.

abstract:
  Abstract Angiotensin-converting enzyme (ACE) is a zinc metalloproteinase and a key regulator of the renin–angiotensin system (RAS). ACE2 is a newly described enzyme identified in rodents and humans with a more restricted distribution than ACE, and is found mainly in heart and kidney. ACE2 cleaves a single residue from angiotensin I (Ang I) to generate Ang 1–9, and degrades Ang II, the main effector of the RAS, to the vasodilator Ang 1–7. The importance of ACE2 in normal physiology and pathophysiological states is largely unknown. ACE2 might act in a counter-regulatory manner to ACE, modulating the balance between vasoconstrictors and vasodilators within the heart and kidney, and playing a significant role in regulating cardiovascular and renal function.


id: cord-332716-1d89j7jh
title: El SRAA y el SARS-CoV-2: el acertijo a resolver
author: Choi, Marcelo
date: 2020-05-27
txt: ./txt/cord-332716-1d89j7jh.txt
cache: ./cache/cord-332716-1d89j7jh.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S1889183720300568?v=s5
doi: 10.1016/j.hipert.2020.05.005
summary:
  Uno de los temas que ha generado debate se vincula con la asociación entre la terapia antihipertensiva con inhibidores del sistema renina-angiotensina-aldosterona (SRAA) y la infección por el virus SARS-CoV-2. Para ingresar a las células el coronavirus interactúa, utilizando como receptor, con la ECA2 y serina-proteasas transmembrana de tipo II (TMPRSS2) ubicadas en la superficie celular del huésped (7) . Los estudios clínicos llevados a cabo hasta el día de hoy no han demostrado que existen diferencias entre ambos tratamientos en términos de aumento del riesgo de infección por SARS-CoV-2 o de desarrollo de resultados graves en pacientes con COVID-19 (27) (28) (29) (30) (31) . Si bien existe evidencia in vitro de que el SARS-CoV-2 se une a los receptores ECA2 y que éstos se encuentran aumentados en presencia de IECA o ARA-II, no hay evidencia al momento de que la exposición a estos fármacos facilite la entrada del coronavirus ni que produzcan un mayor riesgo de COVID-19.

abstract:
  Resumen El 31 de diciembre de 2019 se reportó el primer caso de COVID-19 en Wuhan, China, y desde entonces ha habido un interés creciente y sin precedentes por conocer todos los aspectos vinculados con esta nueva enfermedad. Uno de los temas que ha generado debate se vincula con la asociación entre la terapia antihipertensiva con inhibidores del sistema renina-angiotensina-aldosterona (SRAA) y la infección por el virus SARS-CoV-2. Si bien muchas preguntas siguen hoy día sin poder ser respondidas, la intención de este comunicado es informar a los profesionales de la salud acerca del estado actual de conocimiento. Dado que este es un tema en constante evolución, se recomienda su actualización a medida que se presenten nuevas evidencias. A continuación, daremos revisión a los estudios preclínicos y clínicos que relacionan el coronavirus con el SRAA. Abstract The first case of COVID-19 was reported on 31 December 2019 in Wuhan, China. Ever since there has been unprecedented and growing interest in learning about all aspects of this new disease. Debate has been generated as to the association between antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors and SARS-CoV-2 infection. While many questions as yet remain unanswered, the aim of this report is to inform health professionals about the current state of knowledge. Because this is an ever-evolving topic, the recommendation is that it be updated as new evidence becomes available. Below, we provide a review of pre-clinical and clinical studies that link coronavirus to the RAAS.


id: cord-333580-tw9cehxv
author: Ferrario, Carlos M.
date: 2020-07-24
txt: ./txt/cord-333580-tw9cehxv.txt
cache: ./cache/cord-333580-tw9cehxv.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.dsx.2020.07.041
doi: 10.1016/j.dsx.2020.07.041
abstract: nan
summary:
  title: Commentary on "angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic" In their interesting article which outlines concerns regarding the potential adverse evolution of SARS-CoV-2 infection in diabetic patients medicated with blockers of the renin angiotensin system (RAS), it is incorrectly stated that angiotensin converting enzyme 2 (ACE2; EC 3.4.17.23) hydrolyzes angiotensin-(1-9) [Ang-(1-9)] into angiotensin-(1-7) [Ang-(1-7)]. The second point that needs correction is the suggestion that angiotensin receptor blockers (ARBs) cause a reduction in Ang II levels (plasma, tissue?) in part by upregulation of Ace2 gene transcription and increased enzymatic activity [3] . Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic Increased expression of angiotensin converting enzyme 2 in conjunction with reduction of neointima by angiotensin II type 1 receptor blockade

title:
  Commentary on “angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic”


id: cord-334717-zg9f19p8
title: SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy
author: Chung, Mina K.
date: 2020-08-06
txt: ./txt/cord-334717-zg9f19p8.txt
cache: ./cache/cord-334717-zg9f19p8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32771682/
doi: 10.1016/j.ebiom.2020.102907
summary:
  Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have been reported to increase ACE2 expression in animal models, and worse outcomes are reported in patients with co-morbidities commonly treated with these agents, leading to controversy during the COVID-19 pandemic over whether these drugs might be helpful or harmful. Recently there has been controversy over whether use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) might be harmful in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cardiovascular disease, hypertension, or diabetes mellitus under treatment with these agents. SARS-CoV-2, the coronavirus causing COVID-19, enters host cells via binding of the virus spike protein to angiotensin-converting enzyme 2 (ACE2). In a study of 2877 hospitalized patients with COVID-19, 850 had hypertension of which 183 were treated with renin-angiotensin-aldosterone system inhibitors (RAASi) and 527 were not; RAASi use was not associated with severity of disease or mortality [66] .

abstract:
  BACKGROUND: SARS-CoV-2 enters cells by binding of its spike protein to angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have been reported to increase ACE2 expression in animal models, and worse outcomes are reported in patients with co-morbidities commonly treated with these agents, leading to controversy during the COVID-19 pandemic over whether these drugs might be helpful or harmful. METHODS: : Animal, in vitro and clinical data relevant to the biology of the renin-angiotensin system (RAS), its interaction with the kallikrein-kinin system (KKS) and SARS-CoV-2, and clinical studies were reviewed. FINDINGS AND INTERPRETATION: SARS-CoV-2 hijacks ACE2to invade and damage cells, downregulating ACE2, reducing its protective effects and exacerbating injurious Ang II effects. However, retrospective observational studies do not show higher risk of infection with ACEI or ARB use. Nevertheless, study of the RAS and KKS in the setting of coronaviral infection may yield therapeutic targets.


id: cord-335076-mmpox655
title: Angiotensin II Peptides
author: Izumi, Yasukatsu
date: 2013-03-01
txt: ./txt/cord-335076-mmpox655.txt
cache: ./cache/cord-335076-mmpox655.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/B978012385095900186X
doi: 10.1016/b978-0-12-385095-9.00186-x
summary:
  Ang II, via the Ang II type 1 receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances, and activates multiple intracellular signaling cascades in cardiac myocytes and fibroblasts, as well as vascular endothelial and smooth muscle cells. Recently, new factors have been discovered, such as angiotensin-converting enzyme 2, angiotensin-(1-7), and its receptor Mas. This section summarizes the current knowledge about the broad RAS in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, and atherosclerosis. Ang II infusion stimulated aortic thrombin receptor mRNA expression in rats, which was blocked by either ARB or the heparin-binding chimera of human Cu/Zn superoxide dismutase but not by normalization of blood pressure with hydralazine treatment, suggesting that Ang II increases vascular thrombin receptor by AT 1 R-mediated superoxide production and may be implicated in the pathophysiology of atherosclerosis by thrombin cascade activation.

abstract:
  ABSTRACT Much evidence supports the notion that angiotensin II (Ang II), the central product of the renin–angiotensin system (RAS), may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiovascular diseases in humans. Ang II, via the Ang II type 1 receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances, and activates multiple intracellular signaling cascades in cardiac myocytes and fibroblasts, as well as vascular endothelial and smooth muscle cells. Recently, new factors have been discovered, such as angiotensin-converting enzyme 2, angiotensin-(1-7), and its receptor Mas. This section summarizes the current knowledge about the broad RAS in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, and atherosclerosis.


id: cord-337678-vh6dpf4e
author: Calò, Lorenzo A
date: 2020-08-07
txt: ./txt/cord-337678-vh6dpf4e.txt
cache: ./cache/cord-337678-vh6dpf4e.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32784543/
doi: 10.3390/ijms21165660
summary:
  We suggest that linkage between the specific gene defects identified in GS and BS and the myriad of distinctive and frequently overlapping clinical findings may be the result of aberrant glycosylation of ACE2 driven by altered TGN/endosome system acidification caused by the metabolic alkalosis brought about by these salt-losing tubulopathies in addition to their altered intracellular calcium signaling due to a blunted second messenger induced intracellular calcium release that is, in turn, amplified by the RAS system. Gitelman''s syndrome (GS) is a genetic tubulopathy caused by loss-of-function mutations in the SLC12A3 gene, which encodes the Na + -Cl − cotransporter and is characterized by hypokalemic metabolic alkalosis, hypocalciuria, hypomagnesemia, activated Renin-Angiotensin System (RAS) and high Angiotensin II (Ang II) levels.

title:
  Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype?

abstract:
  Gitelman’s syndrome (GS) and Bartter’s syndrome (BS) are rare inherited salt-losing tubulopathies whose variations in genotype do not correlate well with either clinical course or electrolyte requirements. Using GS/BS patients as nature’s experiments, we found them to be a human model of endogenous Ang II antagonism with activated Renin-Angiotensin System (RAS), resulting in high Ang II levels with blunted cardiovascular effects. These patients are also characterized by increased and directly correlated levels of both Angiotensin Converting Enzyme 2 (ACE2) and Ang 1-7. Understanding the myriad of distinctive and frequently overlapping clinical presentations of GS/BS arises remains challenging. Efforts to find a treatment for COVID-19 has fueled a recent surge in interest in chloroquine/hydroxychloroquine and its effects. Of specific interest are chloroquine/hydroxychloroquine’s ability to inhibit SARS-CoV infection by impairing ACE2, the SARS-CoV2 entry point, through terminal glycosylation via effects on TGN/post-Golgi pH homeostasis. Several different studies with a GS or a BS phenotype, along with a nonsyndromic form of X-linked intellectual disability linked to a mutated SLC9A7, provide additional evidence that specific gene defects can act via misregulation of TGN/post-Golgi pH homeostasis, which leads to a common mechanistic basis resulting in overlapping phenotypes. We suggest that linkage between the specific gene defects identified in GS and BS and the myriad of distinctive and frequently overlapping clinical findings may be the result of aberrant glycosylation of ACE2 driven by altered TGN/endosome system acidification caused by the metabolic alkalosis brought about by these salt-losing tubulopathies in addition to their altered intracellular calcium signaling due to a blunted second messenger induced intracellular calcium release that is, in turn, amplified by the RAS system.


id: cord-339157-wj47xeqj
author: Zhang, Chao
date: 2018-05-23
txt: ./txt/cord-339157-wj47xeqj.txt
cache: ./cache/cord-339157-wj47xeqj.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1371/journal.pone.0197861
doi: 10.1371/journal.pone.0197861
summary:
  RESULTS: The concentrations of Ang II and NA in serum of the HFMD patients with mild or severe symptoms were significantly higher than that in healthy controls. According to the "diagnosis and treatment guideline on hand-foot-and-mouth disease (2010)", patients younger than 60 months with severe symptoms including meningitis, pulmonary edema, and mild cases without any nervous system lesions or pulmonary edema were included in this study. The concentrations of Ang II and NA in serum of the HFMD patients with mild or severe symptoms were significantly higher than that in healthy controls (P<0.001). The concentrations of Ang II and NA in serum of the HFMD patients with mild or severe symptoms were significantly higher than that in healthy controls (P<0.001). In the present study, we found that the concentrations of Ang II and NA were increased in serum of HFMD cases with mild or severe symptoms.

title:
  Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease

abstract:
  BACKGROUND: Hand-foot-and-mouth disease (HFMD) is generally considered as a mild exanthematous disease to infants and young children worldwide. HFMD cases are usually mild and self-limiting but for few cases leads to complicated severe clinical outcomes, and even death. Previous studies have indicated that serum Ang II levels in patients with H7N9 infection were related to the severity of infection. However, the mechanisms underlying the pathogenesis of severe HFMD remain unclear. This study was undertaken to clarify the role of the renin-angiotensin system (RAS) in the progression of severe HFMD. METHODS: In the present study, 162 children including HFMD patients and healthy controls were recruited. The data was analyzed by time-series fashion. Concentrations of angiotensin II (Ang II) and noradrenaline (NA) in serum of patients were measured with ELISA. We established a mouse model for enterovirus 71 (EV71) infection and determined concentrations of Ang II, NA in tissue lysates at 3, 5 and 7 days post infection (dpi). RESULTS: The concentrations of Ang II and NA in serum of the HFMD patients with mild or severe symptoms were significantly higher than that in healthy controls. Additionally, the concentrations of Ang II and NA in serum of severe cases were significantly higher than those mild cases and the increased concentrations of Ang II and NA showed the same time trend during the progression of HFMD in the severe cases. Furthermore, the concentrations of Ang II and NA in target organs of EV71-infected mice including brains, skeletal muscle, and lungs were increased with the progression of EV71 infection in mice. Histopathological alterations were observed in the brains, skeletal muscle and lungs of EV71-infected mice. CONCLUSION: Our study suggested that activation of the RAS is implicated in the pathogenesis of severe HFMD.


id: cord-339752-o6atz33c
author: Xiao, Li
date: 2020-04-28
txt: ./txt/cord-339752-o6atz33c.txt
cache: ./cache/cord-339752-o6atz33c.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/v12050491
doi: 10.3390/v12050491
summary:
  According to a report based on 72,314 cases (test confirmed cases: 44,672 (62%) from the Chinese Center for Disease Control and Prevention, 81% of COVID-19 patients have cold-like symptoms and mild pneumonia, 14% have severe respiratory inflammation, and 5% have critical conditions including respiratory failure, septic shock, and/or multiple organ dysfunction or failure. Similar to SARS (severe acute respiratory syndrome, [2002] [2003] coronavirus (SARS-CoV) [3] , SARS-CoV-2 primarily uses the S protein to invade host cells through ACE2, an enzyme which is known to be important in the renin-angiotensin-aldosterone system (RAAS) [4, 5] . Since TMPRSS2 plays a very important role in SARS-CoV-2 cell entry and ACE2 dysfunction, blocking the activity of TMPRSS2 should be the primary strategy for preventing severe and critical conditions of COVID-19. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)

title:
  ACE2: The Key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?

abstract:
  Recently, the SARS-CoV-2 induced disease COVID-19 has spread all over the world. Nearly 20% of the patients have severe or critical conditions. SARS-CoV-2 exploits ACE2 for host cell entry. ACE2 plays an essential role in the renin–angiotensin–aldosterone system (RAAS), which regulates blood pressure and fluid balance. ACE2 also protects organs from inflammatory injuries and regulates intestinal functions. ACE2 can be shed by two proteases, ADAM17 and TMPRSS2. TMPRSS2-cleaved ACE2 allows SARS-CoV-2 cell entry, whereas ADAM17-cleaved ACE2 offers protection to organs. SARS-CoV-2 infection-caused ACE2 dysfunction worsens COVID-19 and could initiate multi-organ failure. Here, we will explain the role of ACE2 in the pathogenesis of severe and critical conditions of COVID-19 and discuss auspicious strategies for controlling the disease.


id: cord-340581-ngwgb3y0
title: ACE2, COVID-19 Infection, Inflammation, and Coagulopathy: Missing Pieces in the Puzzle
author: Abassi, Zaid
date: 2020-10-06
txt: ./txt/cord-340581-ngwgb3y0.txt
cache: ./cache/cord-340581-ngwgb3y0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33123031/
doi: 10.3389/fphys.2020.574753
summary:
  Angiotensin-converting enzyme is expressed on the plasma membranes of various cell types, including alveolar and intestinal epithelia, vascular endothelial cells in the heart, kidney, and testis, and on macrophages, where it catalyzes the production of Ang 1-7 and its likely paracrine activity (Crackower et al., 2002; Hamming et al., 2007; Santos et al., 2008; Clarke and Turner, 2012; Abassi et al., 2020c) . In this context, testosterone has been described to induce ACE2 expression, the receptor entry of the SARS-CoV-2 infection, but also exerts protective effect against lung injury (Kuba et al., 2005) . FIGURE 2 | Physiology of coronavirus disease 2019 (COVID 19) homing to target host cells expressing ACE2: viral spike-domains enable attachment to cellmembrane-bound ACE2. Thus, viral cellular invasion and replication, initially facilitated by ACE2 and in particular under conditions characterized by enhanced ACE2 expression, later lead to diminution of cell membrane-attached ACE2, and likely increase circulating sACE2 (Figures 2, 3) .

abstract:
  Engulfed by the grave consequences of the coronavirus disease 2019 (COVID-19) pandemic, a better understanding of the unique pattern of viral invasion and virulence is of utmost importance. Angiotensin (Ang)-converting enzyme (ACE) 2 is a key component in COVID-19 infection. Expressed on cell membranes in target pulmonary and intestinal host cells, ACE2 serves as an anchor for initial viral homing, binding to COVID-19 spike-protein domains to enable viral entry into cells and subsequent replication. Viral attachment is facilitated by a multiplicity of membranal and circulating proteases that further uncover attachment loci. Inherent or acquired enhancement of membrane ACE2 expression, likely leads to a higher degree of infection and may explain the predisposition to severe disease among males, diabetics, or patients with respiratory or cardiac diseases. Additionally, once attached, viral intracellular translocation and replication leads to depletion of membranal ACE2 through degradation and shedding. ACE2 generates Ang 1-7, which serves a critical role in counterbalancing the vasoconstrictive, pro-inflammatory, and pro-coagulant effects of ACE-induced Ang II. Therefore, Ang 1-7 may decline in tissues infected by COVID-19, leading to unopposed deleterious outcomes of Ang II. This likely leads to microcirculatory derangement with endothelial damage, profound inflammation, and coagulopathy that characterize the more severe clinical manifestations of COVID-19 infection. Our understanding of COVID-ACE2 associations is incomplete, and some conceptual formulations are currently speculative, leading to controversies over issues such as the usage of ACE inhibitors or Ang-receptor blockers (ARBs). This highlights the importance of focusing on ACE2 physiology in the evaluation and management of COVID-19 disease.


id: cord-342271-m9tn3qu0
title: Angiotensin-converting enzyme 2 and new insights into the renin–angiotensin system
author: Lambert, Daniel W.
date: 2008-02-15
txt: ./txt/cord-342271-m9tn3qu0.txt
cache: ./cache/cord-342271-m9tn3qu0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/17897633/
doi: 10.1016/j.bcp.2007.08.012
summary:
  ACE2 displays homology to two quite distinct proteins; its amino-terminal domain shares approximately 40% sequence identity with ACE, whereas its cytoplasmic and transmembrane domains display 48% homology to collectrin, a non-catalytic protein recently shown to have a critical role in amino acid absorption in the kidney [3, 4] , pancreatic beta cell proliferation [5] and insulin exocytosis [6] . The high level of expression of ACE2 in the heart together with its ability to hydrolyse angiotensin peptides have suggested a role for ACE2 in maintaining cardiovascular physiology from the outset, a hypothesis subsequently supported by experimental data. A role for the RAS in the development of lung disease has been suggested by studies in rodents showing AT1 receptor antagonists protect against experimentally induced pulmonary fibrosis [33] , and an increased mortality rate in acute respiratory distress syndrome (ARDS) patients carrying the ACE DD polymorphism [34] .

abstract:
  Components of the renin–angiotensin system are well established targets for pharmacological intervention in a variety of disorders. Many such therapies abrogate the effects of the hypertensive and mitogenic peptide, angiotensin II, by antagonising its interaction with its receptor, or by inhibiting its formative enzyme, angiotensin-converting enzyme (ACE). At the turn of the millennium, a homologous enzyme, termed ACE2, was identified which increasingly shares the limelight with its better-known homologue. In common with ACE, ACE2 is a type I transmembrane metallopeptidase; however, unlike ACE, ACE2 functions as a carboxypeptidase, cleaving a single C-terminal residue from a distinct range of substrates. One such substrate is angiotensin II, which is hydrolysed by ACE2 to the vasodilatory peptide angiotensin 1–7. In this commentary we discuss the latest developments in the rapidly progressing study of the physiological and patho-physiological roles of ACE2 allied with an overview of the current understanding of its molecular and cell biology. We also discuss parallel developments in the study of collectrin, a catalytically inactive homologue of ACE2 with critical functions in the pancreas and kidney.


id: cord-342478-2k2eb1rk
title: The Actin Bundling Protein Fascin-1 as an ACE2-Accessory Protein
author: Ogunlade, Blessing
date: 2020-08-31
txt: ./txt/cord-342478-2k2eb1rk.txt
cache: ./cache/cord-342478-2k2eb1rk.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s10571-020-00951-x
doi: 10.1007/s10571-020-00951-x
summary:
  We have previously shown that angiotensin-converting enzyme 2 (ACE2), an enzyme counterbalancing the deleterious effects of angiotensin type 1 receptor activation by production of vasodilatory peptides Angiotensin (Ang)-(1–9) and Ang-(1–7), is internalized and degraded in lysosomes following chronic Ang-II treatment. In conclusion, we identified fascin-1 as an ACE2-accessory protein, interacting with the enzyme in an Ang-II dependent manner and contributing to the regulation of enzyme activity. Our group originally demonstrated that Ang-II induces ACE2 internalization and degradation into lysosomes through an Ang-II type 1 receptor (AT 1 R)-dependent mechanism and this process leads to a decrease in the expression levels and activity of the enzyme (Deshotels et al. In the present work, we identify fascin-1 as the only protein which in HEK293T cells has differential interactions with ACE2 after 4 h treatment with Ang-II, a time point that coincides with the lysosomal targeting of this enzyme (Deshotels et al.

abstract:
  We have previously shown that angiotensin-converting enzyme 2 (ACE2), an enzyme counterbalancing the deleterious effects of angiotensin type 1 receptor activation by production of vasodilatory peptides Angiotensin (Ang)-(1–9) and Ang-(1–7), is internalized and degraded in lysosomes following chronic Ang-II treatment. However, the molecular mechanisms involved in this effect remain unknown. In an attempt to identify the accessory proteins involved in this effect, we conducted a proteomic analysis in ACE2-transfected HEK293T cells. A single protein, fascin-1, was found to differentially interact with ACE2 after Ang-II treatment for 4 h. The interactions between fascin-1 and ACE2 were confirmed by confocal microscopy and co-immunoprecipitation. Overexpression of fascin-1 attenuates the effects of Ang-II on ACE2 activity. In contrast, downregulation of fascin-1 severely decreased ACE2 enzymatic activity. Interestingly, in brain homogenates from hypertensive mice, we observed a significant reduction of fascin-1, suggesting that the levels of this protein may change in cardiovascular diseases. In conclusion, we identified fascin-1 as an ACE2-accessory protein, interacting with the enzyme in an Ang-II dependent manner and contributing to the regulation of enzyme activity.


id: cord-343225-8nxsrod5
title: An update on ACE2 amplification and its therapeutic potential
author: Marquez, Alonso
date: 2020-05-29
txt: ./txt/cord-343225-8nxsrod5.txt
cache: ./cache/cord-343225-8nxsrod5.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1111/apha.13513
doi: 10.1111/apha.13513
summary:
  RAS blockade based on inhibiting the formation of Ang II with ACE inhibitors or blocking the activation of the Ang II type 1 (AT1) receptor is a widely used therapy for kidney and cardiovascular disease. has deleterious effects to increase blood pressure and exacerbate cardiac fibrosis in subtotal nephrectomy rats kidney disease model in association with increased cardiac ACE activity 51,52 In one study human recombinant ACE2 was shown to improve diabetic kidney disease in Akita mice 104 . Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice Angiotensin-converting enzyme (ACE) 2 overexpression ameliorates glomerular injury in a rat model of diabetic nephropathy: a comparison with ACE inhibition Angiotensin-converting enzyme 2 amplification limited to the circulation does not protect mice from development of diabetic nephropathy A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

abstract:
  The renin angiotensin system (RAS) plays an important role in the pathogenesis of variety of diseases. Targeting the formation and action of angiotensin II (Ang II), the main RAS peptide, has been the key therapeutic target for last three decades. ACE‐related carboxypeptidase (ACE2), a monocarboxypeptidase that had been discovered 20 years ago, is one of the catalytically most potent enzymes known to degrade Ang II to Ang‐(1‐7), a peptide that is increasingly accepted to have organ ‐protective properties that oppose and counterbalance those of Ang II. In addition to its role as a RAS enzyme ACE2 is the main receptor for SARS‐CoV‐2. In this review, we discuss various strategies that have been used to achieve amplification of ACE2 activity including the potential therapeutic potential of soluble recombinant ACE2 protein and novel shorter ACE2 variants.


id: cord-343736-htwlfqos
title: miRNA-200c-3p is crucial in acute respiratory distress syndrome
author: Liu, Qiang
date: 2017-06-27
txt: ./txt/cord-343736-htwlfqos.txt
cache: ./cache/cord-343736-htwlfqos.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/celldisc.2017.21
doi: 10.1038/celldisc.2017.21
summary:
  Therefore, we identify a shared mechanism of viral and bacterial lung infection-induced ALI/ARDS via nuclear factor-κB-dependent upregulation of miR-200c-3p to reduce ACE2 levels, which leads increased angiotensin II levels and subsequently causes lung injury. Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI), is the main predisposing factor in highly pathogenic avian influenza virus-induced death cases [1, 2] . Additionally, the ACE2 protein expression levels were downregulated in A549 cells (Supplementary Figure S1e) and HEK293T cells (Supplementary Figure S1f) after infection with H5N1 influenza virus, which were consistent with our previous observations in the H5N1-infected mice lung tissues [16] . Our study indicates that miR-200c-3p has a crucial role in the regulation of ACE2 in ALI or ARDS induced by H5N1 virus infection and severe pneumonia.

abstract:
  Influenza infection and pneumonia are known to cause much of their mortality by inducing acute respiratory distress syndrome (ARDS), which is the most severe form of acute lung injury (ALI). Angiotensin-converting enzyme 2 (ACE2), which is a negative regulator of angiotensin II in the renin–angiotensin system, has been reported to have a crucial role in ALI. Downregulation of ACE2 is always associated with the ALI or ARDS induced by avian influenza virus, severe acute respiratory syndrome-coronavirus, respiratory syncytial virus and sepsis. However, the molecular mechanism of the decreased expression of ACE2 in ALI is unclear. Here we show that avian influenza virus H5N1 induced the upregulation of miR-200c-3p, which was then demonstrated to target the 3′-untranslated region of ACE2. Then, we found that nonstructural protein 1 and viral RNA of H5N1 contributed to the induction of miR-200c-3p during viral infection. Additionally, the synthetic analog of viral double-stranded RNA (poly (I:C)), bacterial lipopolysaccharide and lipoteichoic acid can all markedly increase the expression of miR-200c-3p in a nuclear factor-κB-dependent manner. Furthermore, markedly elevated plasma levels of miR-200c-3p were observed in severe pneumonia patients. The inhibition of miR-200c-3p ameliorated the ALI induced by H5N1 virus infection in vivo, indicating a potential therapeutic target. Therefore, we identify a shared mechanism of viral and bacterial lung infection-induced ALI/ARDS via nuclear factor-κB-dependent upregulation of miR-200c-3p to reduce ACE2 levels, which leads increased angiotensin II levels and subsequently causes lung injury.


id: cord-344012-npob20n0
author: Gheblawi, Mahmoud
date: 2020-05-08
txt: ./txt/cord-344012-npob20n0.txt
cache: ./cache/cord-344012-npob20n0.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1161/circresaha.120.317015
doi: 10.1161/circresaha.120.317015
summary:
  ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases. 21, 22 Ongoing global efforts are focused on manipulating the ACE2/Ang 1-7 axis to curtail SARS-CoV-2 infection while affording maximal protective effects against lung and cardiovascular damage in patients with In this review, we summarize the diverse roles of ACE2, highlighting its role as the SARS-CoV-2 receptor and negative regulator of the RAS, and the implications for the COVID-19 pandemic.

title:
  Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2

abstract:
  ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1–7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.


id: cord-346281-sma6e891
author: Maldonado, Valente
date: 2020-06-09
txt: ./txt/cord-346281-sma6e891.txt
cache: ./cache/cord-346281-sma6e891.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32540603/
doi: 10.1016/j.mehy.2020.109988
summary:
  Pentoxifylline (PTX) is a phosphodiesterase inhibitor that increases cyclic adenosine monophosphate levels, which in turn activate protein kinase, leading to a reduction in the synthesis of proinflammatory cytokines to ultimately influence the renin-angiotensin system (RAS) in vitro by inhibiting angiotensin 1 receptor (AT1R) expression. The rheological, anti-inflammatory, and renin-angiotensin axis properties of PTX highlight this drug as a therapeutic treatment alternative for patients with COVID-19 by helping reduce the production of the inflammatory cytokines without deleterious effects on the immune system to delay viral clearance. 5 Overall, the rheological, anti-inflammatory, and renin-angiotensin axis properties of PTX highlight this drug as a therapeutic treatment alternative for patients with COVID-19, which can help reduce the production of the inflammatory cytokines TNF-α, IL-6, IFN-γ, and IL-17 and increase the anti-inflammatory cytokine IL-10.

title:
  Repositioning of pentoxifylline as an immunomodulator and regulator of the renin-angiotensin system in the treatment of COVID-19

abstract:
  Pentoxifylline (PTX) is a phosphodiesterase inhibitor that increases cyclic adenosine monophosphate levels, which in turn activate protein kinase, leading to a reduction in the synthesis of proinflammatory cytokines to ultimately influence the renin-angiotensin system (RAS) in vitro by inhibiting angiotensin 1 receptor (AT1R) expression. The rheological, anti-inflammatory, and renin-angiotensin axis properties of PTX highlight this drug as a therapeutic treatment alternative for patients with COVID-19 by helping reduce the production of the inflammatory cytokines without deleterious effects on the immune system to delay viral clearance. Moreover, PTX can restore the balance of the immune response, reduce damage to the endothelium and alveolar epithelial cells, improve circulation, and prevent microvascular thrombosis. There is further evidence that PTX can improve ventilatory parameters. Therefore, we propose repositioning PTX in the treatment of COVID-19. The main advantage of repositioning PTX is that it is an affordable drug that is already available worldwide with an established safety profile, further offering the possibility of immediately analysing the result of its use and associated success rates. Another advantage is that PTX selectively reduces the concentration of TNF-α mRNA in cells, which, in the case of an acute infectious state such as COVID-19, would seem to offer a more strategic approach.


id: cord-349445-yh6ndtgm
title: Targeting Neprilysin (NEP) pathways: A potential new hope to defeat COVID-19 ghost
author: Mohammed El Tabaa, Manar
date: 2020-05-27
txt: ./txt/cord-349445-yh6ndtgm.txt
cache: ./cache/cord-349445-yh6ndtgm.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0006295220302914
doi: 10.1016/j.bcp.2020.114057
summary:
  Therefore, researchers suggested that the use of angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs), may show a positive trend towards the severe inflammatory reactions and endothelial dysfunction caused by stimulating the function of ACE/Ang II/AT-1 axis and thereby, towards the bad pulmonary effects associated with the COVID-19 infection [29, 30] . Since IL-6 would inactivate endothelial nitric oxide synthase (eNOS), it could disrupt NO production [90] , decreasing its level and inducing a state of oxidative stress that may lead to Ang II-induced impairment in endothelial responses [91] Postulating impaired endothelium functions as a principal factor in the pathogenesis of heart failure, hypertension and diabetes, it will be expected to classify the patients of such diseases as high risk groups for COVID-19 development [92] [93] [94] . Taken into consideration the numerous harmful effects possibly induced by Ang II during COVID-19 pathogenesis, we found that most novel studies aim to use the anti-hypertensive drugs which act either by inhibiting the ACE activity or by blocking AT1 receptor, suggesting that action may mitigate the disease severity in COVID-19 patients.

abstract:
  COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.


id: cord-352004-0mdh1jmo
title: Angiotensin Converting Enzyme 2 (ACE2) in Pregnancy: Preeclampsia and Small for Gestational Age
author: Tamanna, Sonia
date: 2020-09-30
txt: ./txt/cord-352004-0mdh1jmo.txt
cache: ./cache/cord-352004-0mdh1jmo.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fphys.2020.590787
doi: 10.3389/fphys.2020.590787
summary:
  METHODS: We measured maternal plasma levels of Ang peptides and converting enzymes in non-pregnant women (n = 10), in normal pregnant women (n = 59), women delivering small for gestational age babies (SGA, n = 25) across gestation (13–36 weeks) and in women with PE (n = 14) in their third trimester. In this study, we measured ACE, sACE2, Ang-(1-7) and NEP levels in plasma from women with uncomplicated (normal) pregnancies and compared them to levels found in healthy non-pregnant women. A non-parametric Kruskal-Wallis test (with Dunn''s multiple comparison test) was performed to compare ACE, ACE2, NEP and Ang-(1-7) levels and ACE2 activity, ACE2/ACE ratio, and ACE2 activity/ACE2 ratio between non-pregnant women and women with normal pregnancies (at 13, 18, 30, and 36 weeks of gestation). However, the ratio between ACE2 activity and ACE2 levels was significantly decreased in women with SGA pregnancies compared with normal pregnancies (P = 0.005; Figure 4G) , this was significant at 13, 18, and 30 weeks of gestation but not at 36 weeks.

abstract:
  INTRODUCTION: An imbalance in angiotensin (Ang) peptides could contribute to the pathophysiology of preeclampsia (PE) and poor fetal growth. METHODS: We measured maternal plasma levels of Ang peptides and converting enzymes in non-pregnant women (n = 10), in normal pregnant women (n = 59), women delivering small for gestational age babies (SGA, n = 25) across gestation (13–36 weeks) and in women with PE (n = 14) in their third trimester. RESULTS: Plasma ACE, ACE2, and Ang-(1-7) levels, and ACE2 activity were significantly higher in normal pregnant women compared with non-pregnant women; neprilysin (NEP) levels were not changed. In SGA pregnancies, ACE and ACE2 levels were higher in early-mid pregnancy compared with normal pregnant women. In women with PE, plasma ACE, ACE2, NEP, and Ang-(1-7) levels and ACE2 activity were lower than levels in normal pregnant women. CONCLUSION: The higher plasma ACE2 levels and activity in pregnancy could be driving the higher Ang-(1-7) levels. The early gestation increases in ACE and ACE2 levels in SGA pregnancies highlights the possibility that these enzymes could be used as potential early biomarkers of poor fetal growth. In women with PE, the reduced ACE2 and NEP levels at term, could be contributing to the reduction in Ang-(1-7) levels. These findings suggest that dysfunctional relationships between two key enzymes in the circulating RAS are involved in the pathogenesis of PE and SGA. Since soluble ACE2 can prevent binding of the novel coronavirus, SARS-CoV-2, to membrane bound ACE2, the interplay between ACE2 and the coronavirus and its impact in pregnancy requires further investigation.


