Summary of your 'study carrel' ============================== This is a summary of your Distant Reader 'study carrel'. The Distant Reader harvested & cached your content into a collection/corpus. It then applied sets of natural language processing and text mining against the collection. The results of this process was reduced to a database file -- a 'study carrel'. The study carrel can then be queried, thus bringing light specific characteristics for your collection. These characteristics can help you summarize the collection as well as enumerate things you might want to investigate more closely. This report is a terse narrative report, and when processing is complete you will be linked to a more complete narrative report. Eric Lease Morgan Number of items in the collection; 'How big is my corpus?' ---------------------------------------------------------- 73 Average length of all items measured in words; "More or less, how big is each item?" ------------------------------------------------------------------------------------ 6322 Average readability score of all items (0 = difficult; 100 = easy) ------------------------------------------------------------------ 45 Top 50 statistically significant keywords; "What is my collection about?" ------------------------------------------------------------------------- 53 Ang 37 ACE2 17 SARS 14 Ang-(1 13 RAS 8 COVID-19 7 ace 4 cell 4 angiotensin 4 Angiotensin 4 ANG 4 ACE 3 RAAS 3 Mas 3 Ang-2 3 ACE-2 2 receptor 2 effect 2 Fig 1 synthesis 1 study 1 structure 1 residue 1 renin 1 protein 1 podocyte 1 peptide 1 patient 1 mouse 1 injury 1 inhibitor 1 group 1 figure 1 enzyme 1 endothelial 1 endocan 1 dna 1 covid-19 1 amino 1 activity 1 acid 1 Wnt 1 VEGF 1 University 1 Tie2 1 TNF 1 SPPS 1 RL-14 1 Phe 1 PTX Top 50 lemmatized nouns; "What is discussed?" --------------------------------------------- 2944 angiotensin 2653 receptor 2316 cell 1663 effect 1641 enzyme 1640 peptide 1361 expression 1353 study 1319 patient 1315 protein 1225 system 1224 activity 1193 level 1139 renin 1117 disease 1114 mouse 1071 role 1061 inhibitor 1008 rat 911 heart 905 ace 857 lung 811 tissue 714 blood 700 kidney 689 function 679 % 668 hypertension 655 acid 642 type 622 infection 622 activation 607 gene 590 injury 572 pathway 568 pressure 543 group 535 response 533 model 532 treatment 514 inhibition 497 mechanism 496 action 486 factor 482 brain 473 axis 454 result 450 failure 433 coronavirus 426 structure Top 50 proper nouns; "What are the names of persons or places?" -------------------------------------------------------------- 3454 ACE2 3304 Ang 3131 II 1361 al 1207 SARS 1158 et 1023 Ang-(1 961 RAS 919 ACE 657 CoV-2 601 COVID-19 530 Angiotensin 529 . 311 Mas 307 Fig 261 I 251 CoV 247 AT 244 ACE-2 239 RAAS 222 C 206 ANG 193 podocyte 168 AT1R 167 Angiotensin-(1 161 angiotensinogen 149 ARDS 148 ARB 143 de 142 Ang-2 136 mRNA 133 IV 132 losartan 128 la 122 NEP 117 RNA 116 China 115 III 115 AT1 114 N 113 Ang-1 112 TMPRSS2 109 7 106 S 105 TGF 103 angiotensin 97 Apelin 96 mg 93 α 91 TNF Top 50 personal pronouns nouns; "To whom are things referred?" ------------------------------------------------------------- 984 we 886 it 395 i 219 they 76 them 30 us 18 itself 8 he 7 you 7 themselves 7 one 4 sfrp2 2 s 2 imagej 2 endothelin-1 2 atp6ap2 1 upa 1 thymosin-2 1 tace 1 ours 1 nsp15 1 mg 1 http://101.96.8.164/www Top 50 lemmatized verbs; "What do things do?" --------------------------------------------- 11991 be 2436 have 1353 convert 1216 increase 1174 induce 1008 show 878 use 684 reduce 615 mediate 548 bind 547 associate 478 include 464 find 455 suggest 445 lead 405 inhibit 398 express 363 regulate 356 involve 351 report 348 activate 334 result 333 do 324 compare 323 decrease 301 demonstrate 298 base 293 cause 290 know 287 relate 286 identify 275 signal 269 treat 268 follow 259 provide 257 produce 254 indicate 249 protect 248 play 247 promote 245 prevent 235 contribute 234 contain 229 develop 228 improve 224 enhance 224 attenuate 220 stimulate 220 observe 219 form Top 50 lemmatized adjectives and adverbs; "How are things described?" --------------------------------------------------------------------- 1059 also 949 - 948 not 947 human 757 high 646 cardiac 529 other 519 renal 503 acute 500 vascular 485 such 483 however 475 inflammatory 461 clinical 447 endothelial 442 cardiovascular 431 severe 409 well 384 viral 383 new 381 specific 379 more 372 pulmonary 356 important 348 novel 347 respiratory 344 different 338 several 329 active 328 low 327 further 302 myocardial 298 first 298 anti 292 therapeutic 279 hypertensive 274 only 268 diabetic 267 potential 266 functional 265 as 259 significant 252 thus 252 significantly 246 cellular 244 most 243 normal 242 chronic 236 molecular 232 dependent Top 50 lemmatized superlative adjectives; "How are things described to the extreme?" ------------------------------------------------------------------------- 79 most 43 least 34 high 24 good 18 Most 7 late 4 short 4 large 3 strong 3 small 3 simple 3 long 3 great 2 low 2 bad 1 poor 1 new 1 i+1 1 few 1 early 1 close 1 c(-Pro 1 big 1 -β 1 -t Top 50 lemmatized superlative adverbs; "How do things do to the extreme?" ------------------------------------------------------------------------ 165 most 33 least 4 well 1 highest 1 early Top 50 Internet domains; "What Webbed places are alluded to in this corpus?" ---------------------------------------------------------------------------- 2 doi.org 2 creativecommons.org 2 coronavirus.jhu.edu 1 www.proteinatlas.org 1 www.ncbi.nlm.nih.gov 1 www.gestation.net 1 www.genecards.org 1 www.frontiersin.org 1 www.covid19cellatlas.org 1 www.cancer.org 1 rgd.mcw.edu 1 rfam.xfam 1 bgee.org 1 alfred 1 101.96.8.164 1 101 Top 50 URLs; "What is hyperlinked from this corpus?" ---------------------------------------------------- 2 http://creativecommons.org/licenses/by/4.0/ 1 http://www.proteinatlas.org/ENSG00000130234-ACE2/tissue 1 http://www.ncbi.nlm.nih.gov/LocusLink/ 1 http://www.gestation.net/ 1 http://www.genecards.org/cgi-bin/carddisp.pl?gene=ACE2#protein_expression 1 http://www.frontiersin.org/articles/10.3389/fphys 1 http://www.covid19cellatlas.org/ 1 http://www.cancer.org/cancer/ 1 http://rgd.mcw.edu/rgdweb/report/strain/main.html?id=5131952 1 http://rfam.xfam 1 http://doi.org/10.1371/journal.pone.0197861.g005 1 http://doi.org/10.1038/s41401-020-0375-9 1 http://coronavirus.jhu.edu/map.html 1 http://coronavirus.jhu.edu/ 1 http://bgee.org/?page=gene&gene_id=ENSG00000130234 1 http://alfred 1 http://101.96.8.164/www 1 http://101 Top 50 email addresses; "Who are you gonna call?" ------------------------------------------------- 1 yangxiuhong@ncst.edu.cn 1 walmor.de-mello@upr.edu 1 frej.fyhrquist@helsinki.fi 1 a.j.turner@leeds.ac.uk Top 50 positive assertions; "What sentences are in the shape of noun-verb-noun?" ------------------------------------------------------------------------------- 197 angiotensin converting enzyme 18 ace2 is also 13 ace2 is not 9 receptor binding domain 8 activity was significantly 8 levels were significantly 6 ii mediates angiotensin 5 ace2 converts ang 5 ace2 is highly 5 ace2 is widely 5 activity was not 5 cells expressing ace2 5 ii did not 5 rats reduces blood 5 system is not 4 ace is also 4 ace2 did not 4 ace2 does not 4 activity is not 4 activity was also 4 cells are not 4 expression is up 4 studies do not 3 ace2 has also 3 ace2 has only 3 ace2 has recently 3 ace2 induces tnf 3 ace2 is critical 3 expression was also 3 expression was not 3 expression was significantly 3 ii induces apoptosis 3 inhibitors do not 3 levels were also 3 levels were not 3 levels were positively 3 mice showed non 3 receptors are also 3 receptors regulate ace2 3 renin is not 3 study did not 3 study was also 2 ace mediated formation 2 ace2 are also 2 ace2 are type 2 ace2 is mainly 2 ace2 is most 2 ace2 is predominantly 2 ace2 is sufficient 2 ace2 is unaffected Top 50 negative assertions; "What sentences are in the shape of noun-verb-no|not-noun?" --------------------------------------------------------------------------------------- 3 system is not able 2 inhibitors do not completely 2 system is not only 1 ace has no other 1 ace2 had no effect 1 ace2 has no effect 1 ace2 is not important 1 ace2 is not limited 1 ace2 is not necessary 1 ace2 is not only 1 ace2 is not particularly 1 ace2 show no homology 1 activity is not sensitive 1 activity was not significantly 1 activity was not sufficient 1 activity were not significantly 1 cell has no escape 1 cells are not able 1 disease is not clearly 1 effect was no longer 1 effects are not fully 1 effects have not yet 1 expression do not always 1 expression does not significantly 1 expression has not yet 1 ii is not well 1 inhibitor do not completely 1 inhibitors are not markedly 1 levels did not significantly 1 levels is not feasible 1 levels is not yet 1 levels were not significantly 1 mice was not evident 1 patients increased not only 1 protein is not always 1 protein is not only 1 ras are not yet 1 renin is not locally 1 renin is not only 1 renin was no longer 1 studies do not strongly 1 study have no cytotoxic 1 system had no role 1 system has not yet A rudimentary bibliography -------------------------- id = cord-340581-ngwgb3y0 author = Abassi, Zaid title = ACE2, COVID-19 Infection, Inflammation, and Coagulopathy: Missing Pieces in the Puzzle date = 2020-10-06 keywords = ACE2; Ang; SARS 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) . doi = 10.3389/fphys.2020.574753 id = cord-006087-hynkb0a8 author = Acharya, K. Ravi title = Ace revisited: A new target for structure-based drug design date = 2003 keywords = ACE; Ang; inhibitor 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. doi = 10.1038/nrd1227 id = cord-304976-egbl3ljp author = Allen, A.M. title = Neuronal Angiotensin date = 2008-11-05 keywords = Ang; Aogen 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. doi = 10.1016/b978-008045046-9.02053-2 id = cord-330558-autprmr4 author = Burrell, Louise M. title = ACE2, a new regulator of the renin–angiotensin system date = 2004-05-31 keywords = ACE2; Ang 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. doi = 10.1016/j.tem.2004.03.001 id = cord-320331-wtxja5i9 author = Cabbab, Iris Louise N. title = Anti-Inflammatory Drugs and the Renin-Angiotensin-Aldosterone System: Current Knowledge and Potential Effects on Early SARS-CoV-2 Infection date = 2020-10-08 keywords = ACE2; Ang; COVID-19; RAAS; SARS 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] . doi = 10.1016/j.virusres.2020.198190 id = cord-337678-vh6dpf4e author = Calò, Lorenzo A 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? date = 2020-08-07 keywords = ACE2; Ang 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. doi = 10.3390/ijms21165660 id = cord-018009-8j40876m author = Campbell, Duncan J. John title = ACE Inhibition in Heart Failure and Ischaemic Heart Disease date = 2007 keywords = Ang; ace; effect 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 doi = 10.1007/978-1-4020-6372-5_2 id = cord-017585-0llgr357 author = Chappell, Mark C. title = Role of ACE, ACE2 and Neprilysin in the Kidney date = 2007 keywords = ACE2; Ang-(1; ace 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 . doi = 10.1007/978-1-4020-6372-5_1 id = cord-332716-1d89j7jh author = Choi, Marcelo title = El SRAA y el SARS-CoV-2: el acertijo a resolver date = 2020-05-27 keywords = Ang; COVID-19; ECA2; SARS 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. doi = 10.1016/j.hipert.2020.05.005 id = cord-291137-09a3tblt author = Chow, Jonathan H. title = Angiotensin II for the Treatment of COVID-19–Related Vasodilatory Shock date = 2020-04-20 keywords = Ang-2 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). doi = 10.1213/ane.0000000000004825 id = cord-334717-zg9f19p8 author = Chung, Mina K. title = SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy date = 2020-08-06 keywords = ACE2; ARB; Ang; SARS 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] . doi = 10.1016/j.ebiom.2020.102907 id = cord-307894-pfsztifl author = Clarke, Nicola E. title = Chapter 100 Angiotensin-Converting Enzyme-2 date = 2013-12-31 keywords = ACE2; Ang; angiotensin 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 doi = 10.1016/b978-0-12-382219-2.00100-9 id = cord-259933-ggx4v0bz author = Dalan, Rinkoo title = The ACE-2 in COVID-19: Foe or Friend? date = 2020-04-27 keywords = ACE-2; Ang; SARS 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. doi = 10.1055/a-1155-0501 id = cord-274259-voyzq05n author = De Mello, Walmor C. title = Regulation of cell volume and water transport – An old fundamental role of the renin angiotensin aldosterone system components at the cellular level date = 2014-06-16 keywords = Ang; cell 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. doi = 10.1016/j.peptides.2014.06.003 id = cord-001961-0ic7twhy author = Ding, Dan title = Vaccination against type 1 angiotensin receptor prevents streptozotocin-induced diabetic nephropathy date = 2015-09-26 keywords = Ang; RAS 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] . doi = 10.1007/s00109-015-1343-6 id = cord-309619-glb2y82u author = Domingo, Pere title = The four horsemen of a viral Apocalypse: The pathogenesis of SARS-CoV-2 infection (COVID-19) date = 2020-07-29 keywords = ACE2; Ang; COVID-19; IFN; SARS; TNF 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. doi = 10.1016/j.ebiom.2020.102887 id = cord-015859-5kt59ose author = Esch, Joep H.M. Van title = Local Angiotensin Generation and AT(2) Receptor Activation date = 2007 keywords = ACE; Ang; receptor 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. doi = 10.1007/978-1-4020-6372-5_12 id = cord-016335-z2movens author = Ferrario, Carlos M. title = Regulation of Cardiovascular Control Mechanisms by Angiotensin-(1–7) and Angiotensin-Converting Enzyme 2 date = 2010-06-15 keywords = ACE2; Ang-(1 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) . doi = 10.1007/978-1-59259-987-5_3 id = cord-333580-tw9cehxv author = Ferrario, Carlos M. title = Commentary on “angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic” date = 2020-07-24 keywords = Ang-(1 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 doi = 10.1016/j.dsx.2020.07.041 id = cord-000570-0qkzd2w4 author = Ferreira, Anderson J. title = New Cardiovascular and Pulmonary Therapeutic Strategies Based on the Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas Receptor Axis date = 2012-01-26 keywords = ACE2; Ang-(1; Mas 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] . doi = 10.1155/2012/147825 id = cord-313664-qq0h68vc author = Fyhrquist, F. title = Renin‐angiotensin system revisited date = 2008-08-08 keywords = ACE2; Ang; RAS 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. doi = 10.1111/j.1365-2796.2008.01981.x id = cord-318327-9sh2eksm author = Garg, M. title = Review article: the pathophysiological roles of the renin–angiotensin system in the gastrointestinal tract date = 2012-01-05 keywords = ACE; Ang; RAS; angiotensin 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. doi = 10.1111/j.1365-2036.2011.04971.x id = cord-326223-q6e60nf8 author = Gembardt, Florian title = Organ-specific distribution of ACE2 mRNA and correlating peptidase activity in rodents date = 2005-02-16 keywords = ACE2; Ang-(1; Germany; mouse 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. doi = 10.1016/j.peptides.2005.01.009 id = cord-344012-npob20n0 author = Gheblawi, Mahmoud 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 date = 2020-05-08 keywords = ACE2; Ang; COVID-19; RAS; SARS; angiotensin 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. doi = 10.1161/circresaha.120.317015 id = cord-002632-6he8sjpf author = Goldstein, Benjamin title = Alterations in Gene Expression of Components of the Renin-Angiotensin System and Its Related Enzymes in Lung Cancer date = 2017-07-16 keywords = Ang; RAS 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 ). doi = 10.1155/2017/6914976 id = cord-277766-rxmpi61o author = Guang, Cuie title = Three key proteases – angiotensin-I-converting enzyme (ACE), ACE2 and renin – within and beyond the renin-angiotensin system date = 2012-06-15 keywords = ACE2; Ang; RAS; ace; angiotensin; renin 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 doi = 10.1016/j.acvd.2012.02.010 id = cord-303394-iqepytyd author = Han, Su-Xia title = Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: Possible involvement of angiotensin-converting enzyme-2 date = 2010-05-15 keywords = ACE2; Ang; PAH 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. doi = 10.1016/j.taap.2010.02.009 id = cord-278265-hgggkr5y author = Hisatake, Shinji title = The serum angiotensin-converting enzyme 2 and angiotensin-(1-7) concentrations after optimal therapy for acute decompensated heart failure with reduced ejection fraction date = 2020-06-15 keywords = ACE2; Ang-(1 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. doi = 10.1042/bsr20192701 id = cord-006302-pnnkfid0 author = Ioakeimidou, A. title = Increase of circulating endocan over sepsis follow-up is associated with progression into organ dysfunction date = 2017-04-28 keywords = Ang-2; endocan; patient 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. doi = 10.1007/s10096-017-2988-6 id = cord-335076-mmpox655 author = Izumi, Yasukatsu title = Angiotensin II Peptides date = 2013-03-01 keywords = Ang; RAS 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. doi = 10.1016/b978-0-12-385095-9.00186-x id = cord-273595-fkk4ry62 author = Jing, Yan title = Potential influence of COVID-19/ACE2 on the female reproductive system date = 2020-05-04 keywords = ACE2; Ang-(1 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 doi = 10.1093/molehr/gaaa030 id = cord-002307-gk84fnb9 author = Kehoe, Patrick Gavin title = Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology date = 2016-11-25 keywords = ACE-2; Ang 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). doi = 10.1186/s13195-016-0217-7 id = cord-001982-arczqdza author = Khajah, Maitham A. title = Anti-Inflammatory Action of Angiotensin 1-7 in Experimental Colitis date = 2016-03-10 keywords = ACE2; Ang; DSS; Fig 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. doi = 10.1371/journal.pone.0150861 id = cord-275676-fsumpj4n author = Kintscher, Ulrich 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 date = 2020-09-08 keywords = Ang 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). doi = 10.1161/hypertensionaha.120.15841 id = cord-007267-r3gfr1gk author = Kondo, Masateru title = Xanthine Oxidase Inhibition by Febuxostat in Macrophages Suppresses Angiotensin II-Induced Aortic Fibrosis date = 2018-10-23 keywords = Ang; FEB 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. doi = 10.1093/ajh/hpy157 id = cord-342271-m9tn3qu0 author = Lambert, Daniel W. title = Angiotensin-converting enzyme 2 and new insights into the renin–angiotensin system date = 2008-02-15 keywords = ACE2; Ang 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] . doi = 10.1016/j.bcp.2007.08.012 id = cord-006553-0rmuvb5i author = Lew, Rebecca A. title = Characterization of Angiotensin Converting Enzyme-2 (ACE2) in Human Urine date = 2006-05-05 keywords = ACE2; Ang 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) . doi = 10.1007/s10989-006-9031-6 id = cord-343736-htwlfqos author = Liu, Qiang title = miRNA-200c-3p is crucial in acute respiratory distress syndrome date = 2017-06-27 keywords = ACE2; Ang; H5N1; figure 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. doi = 10.1038/celldisc.2017.21 id = cord-007707-c38fu1jv author = Lu, Chen-Chen title = Role of Podocyte Injury in Glomerulosclerosis date = 2019-06-19 keywords = Ang; GBM; RAS; injury; podocyte 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. doi = 10.1007/978-981-13-8871-2_10 id = cord-311099-59pnm4fn author = Lubel, John S title = Liver disease and the renin–angiotensin system: Recent discoveries and clinical implications date = 2008-06-28 keywords = ACE; Ang; Ang-(1; RAS 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. doi = 10.1111/j.1440-1746.2008.05461.x id = cord-277669-uujny2dm author = Lumpuy-Castillo, Jairo title = Cardiovascular Damage in COVID-19: Therapeutic Approaches Targeting the Renin-Angiotensin-Aldosterone System date = 2020-09-04 keywords = ACE2; Ang-(1; Angiotensin; COVID-19; SARS 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] . doi = 10.3390/ijms21186471 id = cord-291595-8241pjpe author = Mahmudpour, Mehdi title = COVID-19 cytokine storm: The anger of inflammation date = 2020-05-30 keywords = ACE2; Ang; COVID-19; SARS 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. doi = 10.1016/j.cyto.2020.155151 id = cord-346281-sma6e891 author = Maldonado, Valente title = Repositioning of pentoxifylline as an immunomodulator and regulator of the renin-angiotensin system in the treatment of COVID-19 date = 2020-06-09 keywords = Ang; COVID-19; PTX; SARS 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. doi = 10.1016/j.mehy.2020.109988 id = cord-343225-8nxsrod5 author = Marquez, Alonso title = An update on ACE2 amplification and its therapeutic potential date = 2020-05-29 keywords = ACE2; Ang; Angiotensin; enzyme 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 doi = 10.1111/apha.13513 id = cord-349445-yh6ndtgm author = Mohammed El Tabaa, Manar title = Targeting Neprilysin (NEP) pathways: A potential new hope to defeat COVID-19 ghost date = 2020-05-27 keywords = ACE-2; Ang; Angiotensin; COVID-19; NEP; RAS; SARS 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. doi = 10.1016/j.bcp.2020.114057 id = cord-318358-glbr8kxh author = Naik, George O A title = COVID-19 and the RAAS date = 2020-06-20 keywords = Ang 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 doi = 10.1093/cid/ciaa818 id = cord-006439-q7m4srvp author = Nakagawa, Pablo title = The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation date = 2020-01-10 keywords = ANG; PRR; RAS 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. doi = 10.1007/s11906-019-1011-2 id = cord-297178-moxhk2e0 author = Novaes Rocha, Vinicius title = Viral replication of SARS-CoV-2 could be self-limitative - the role of the renin-angiotensin system on COVID-19 pathophysiology date = 2020-10-01 keywords = ACE2; Ang; SARS 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) doi = 10.1016/j.mehy.2020.110330 id = cord-298490-p1msabl5 author = Obukhov, Alexander G. title = SARS-CoV-2 Infections and ACE2: Clinical Outcomes Linked With Increased Morbidity and Mortality in Individuals With Diabetes date = 2020-07-15 keywords = ACE2; Ang; RAS; SARS 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. doi = 10.2337/dbi20-0019 id = cord-342478-2k2eb1rk author = Ogunlade, Blessing title = The Actin Bundling Protein Fascin-1 as an ACE2-Accessory Protein date = 2020-08-31 keywords = ACE2; Ang 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. doi = 10.1007/s10571-020-00951-x id = cord-005931-iggkxbbf author = Phillips, M. Ian title = Brain renin angiotensin in disease date = 2008-04-02 keywords = ANG; RAS; ace 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. doi = 10.1007/s00109-008-0331-5 id = cord-325610-n3zb36am author = Postlethwait, John H. 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 date = 2020-09-02 keywords = Ang; Angiotensin 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. doi = 10.1101/2020.09.01.278366 id = cord-012747-s4wf0pix author = Prehn, Jochen H M title = Angiogenin and tRNA fragments in Parkinson’s disease and neurodegeneration date = 2020-03-06 keywords = ANG; Angiogenin 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 doi = 10.1038/s41401-020-0375-9 id = cord-273136-hrgtaunt author = Rabelo, Luiza A. title = Animal Models with a Genetic Alteration of the ACE2/Ang-(1-7)/Mas Axis date = 2015-04-24 keywords = ACE2; Ang-(1; Mas 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. doi = 10.1016/b978-0-12-801364-9.00022-5 id = cord-310124-3bc8zeww author = Ratajczak, Mariusz Z. 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 date = 2020-07-20 keywords = ACE2; Ang; Nlrp3; SARS 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) . doi = 10.1007/s12015-020-10010-z id = cord-006082-x1kankxd author = Romero, Cesar A. title = Novel RAAS agonists and antagonists: clinical applications and controversies date = 2015-02-10 keywords = Ang; RAAS; ace; effect; receptor 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. doi = 10.1038/nrendo.2015.6 id = cord-291146-f3e5ynhu author = Sarangarajan, Rangaprasad 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 date = 2020-09-08 keywords = Ang; ace; covid-19 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. doi = 10.1007/s40615-020-00853-0 id = cord-317888-ei598viq author = Sarzani, Riccardo title = Antagonizing the renin–angiotensin–aldosterone system in the era of COVID-19 date = 2020-05-18 keywords = Ang 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 doi = 10.1007/s11739-020-02365-5 id = cord-252193-pgr07l9b author = Sato, Teruki title = Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling date = 2019-01-09 keywords = Ang; Apelin 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. doi = 10.3390/ijms20020239 id = cord-287207-z6ddajd6 author = Shenoy, Vinayak title = Angiotensin-Converting Enzyme 2/Angiotensin-(1-7)/Mas Receptor Axis: Emerging Pharmacological Target for Pulmonary Diseases date = 2015-04-24 keywords = ACE2; Ang-(1 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. doi = 10.1016/b978-0-12-801364-9.00038-9 id = cord-026680-ksacxsdk author = Shoieb, Sherif M. title = Resveratrol attenuates angiotensin II-induced cellular hypertrophy through the inhibition of CYP1B1 and the cardiotoxic mid-chain HETE metabolites date = 2020-06-12 keywords = Ang; CYP1B1; RL-14 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. doi = 10.1007/s11010-020-03777-9 id = cord-276192-sgts963l author = Simões e Silva, Ana Cristina title = 2020 update on the renin–angiotensin–aldosterone system in pediatric kidney disease and its interactions with coronavirus date = 2020-09-29 keywords = ACE2; AT1R; Ang; Ang-(1; Mas; RAAS 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] . doi = 10.1007/s00467-020-04759-1 id = cord-352004-0mdh1jmo author = Tamanna, Sonia title = Angiotensin Converting Enzyme 2 (ACE2) in Pregnancy: Preeclampsia and Small for Gestational Age date = 2020-09-30 keywords = ACE2; Ang-(1 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. doi = 10.3389/fphys.2020.590787 id = cord-299960-ounktxxv author = Varagic, Jasmina title = New angiotensins date = 2008-04-25 keywords = ACE2; Ang-(1 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. doi = 10.1007/s00109-008-0340-4 id = cord-322212-8xrehbd1 author = Wang, Hanyin title = Unexpected BP Sensitivity to Angiotensin II in a Patient With Coronavirus Disease 2019, ARDS, and Septic Shock date = 2020-04-23 keywords = Ang-2; SARS 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. doi = 10.1016/j.chest.2020.04.015 id = cord-028640-kxrmzyo8 author = Wei, Wen-Ying title = Secreted frizzled-related protein 2 prevents pressure-overload-induced cardiac hypertrophy by targeting the Wnt/β-catenin pathway date = 2020-07-06 keywords = Ang; Fig; Wnt 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. doi = 10.1007/s11010-020-03802-x id = cord-314102-8jf3fnqe author = Wu, Jie title = Advances in research on ACE2 as a receptor for 2019-nCoV date = 2020-08-11 keywords = ACE2; Ang; SARS; cell 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. doi = 10.1007/s00018-020-03611-x id = cord-326405-3446eyi3 author = Wysocki, Jan title = Angiotensin-converting enzyme 2: Possible role in hypertension and kidney disease date = 2008-02-07 keywords = ACE2; ANG; ace 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 doi = 10.1007/s11906-008-0014-1 id = cord-339752-o6atz33c author = Xiao, Li title = ACE2: The Key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel? date = 2020-04-28 keywords = ACE2; Ang; SARS 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) doi = 10.3390/v12050491 id = cord-339157-wj47xeqj author = Zhang, Chao title = Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease date = 2018-05-23 keywords = Ang; HFMD 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. doi = 10.1371/journal.pone.0197861 id = cord-317472-6ese0c0e author = Zisman, Lawrence S. title = ACE and ACE2: a tale of two enzymes date = 2005-02-01 keywords = ACE2; Ang 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 doi = 10.1093/eurheartj/ehi043 id = cord-023225-5quigar4 author = nan title = Posters date = 2012-08-21 keywords = Aib; Ang; Cys; Fmoc; Gly; HPLC; Ile; Leu; Lys; NMR; PNA; Phe; SPPS; University; acid; activity; amino; cell; dna; group; peptide; protein; residue; structure; study; synthesis 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. doi = 10.1002/psc.2449 id = cord-000072-2ygb80sc author = van Meurs, Matijs title = Bench-to-bedside review: Angiopoietin signalling in critical illness – a future target? date = 2009-03-09 keywords = Ang-1; Tie2; VEGF; cell; endothelial 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 doi = 10.1186/cc7153