key: cord-0700338-tx3hfviu
authors: Xu, Baohui; Li, Gang; Guo, Jia; Ikezoe, Toru; Kasirajan, Karthikeshwar; Zhao, Sihai; Dalman, Ronald L.
title: Angiotensin-converting enzyme 2, coronavirus disease 2019 and abdominal aortic aneurysms
date: 2021-02-15
journal: J Vasc Surg
DOI: 10.1016/j.jvs.2021.01.051
sha: 295e0172a6c6bb35992e7c45d30a539a23323c13
doc_id: 700338
cord_uid: tx3hfviu

OBJECTIVE: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the etiologic agent of the current, world-wide coronavirus disease 2019 (COVID-19) pandemic. Angiotensin-converting enzyme 2 (ACE2) is the SARS-CoV-2 host entry receptor for cellular inoculation and target organ injury. We reviewed ACE2 expression and the role of ACE2 - angiotensin 1-7- Mas receptor axis activity in abdominal aortic aneurysm (AAA) pathogenesis to identify potential COVID-19 influences on AAA disease pathogenesis. METHODS: A comprehensive literature search was performed on PubMed, National Library of Medicine, USA. Key words included COVID-19, SARS-CoV-2, AAA, ACE2, ACE or angiotensin II type 1 (AT1) receptor inhibitor, angiotensin 1-7, Mas receptor, age, gender, respiratory diseases, diabetes, autoimmune diseases. Key publications on the epidemiology and pathogenesis of COVID-19 and AAAs were identified and reviewed. RESULTS: All vascular structural cells, including endothelial and smooth muscle cells, fibroblasts and pericytes express ACE2. Cigarette smoking, diabetes, chronic obstructive pulmonary disease, lupus, certain types of malignancies and viral infection promote ACE2 expression and activity, with the magnitude of response varying by sex and age. Genetic deficiency of AT1 receptor, or pharmacological ACE or AT1 inhibition also increases ACE2 and its catalytic product angiotensin 1-7. Genetic ablation or pharmacological inhibition of ACE2 or Mas receptor augments, whereas ACE2 activation or angiotensin 1-7 treatment attenuates, progression of experimental AAAs. Potential influences of SARS-CoV-2 on AAA pathogenesis include augmented ACE-angiotensin II-AT1 receptor activity resulting from reduced reciprocal ACE2-angiotensin 1-7-Mas activation; increased production of proaneurysmal mediators stimulated by viral spike proteins in ACE2-negative myeloid cells or by ACE2-expressing vascular structural cells; augmented local or systemic cross-talk between viral targeted non-vascular, non-leukocytic ACE2-expressing cells via ligand recognition of their cognate leukocyte receptors; and hypoxemia and increased systemic inflammatory tone experienced during severe COVID-19 illness. CONCLUSION: COVID-19 may theoretically influence AAA disease through multiple SARS-CoV-2-induced mechanisms. Further investigation and clinical follow-up will be necessary to determine whether and to what extent the COVID-19 pandemic will influence the prevalence, progression and lethality of AAA disease in the coming decade.

Abdominal aortic aneurysm (AAA) is a common and lethal disease of mature adults 16 worldwide. The prevalence and progression of the disease is influenced by the age, sex, race, 17 tobacco consumption, exercise habits, comorbidities and medication regimens of affected 18 individuals [1] [2] [3] [4] [5] . Although the implementation of targeted screening programs for at-risk 19 individuals and reduced surgical risk associated with endovascular repair has substantially 20 reduced aneurysm-specific mortality 6 , nearly 10,000 Americans died due to rupture or other Published results are inconsistent regarding the importance of ACE2 in the pathogenesis 13 of experimental AAAs not initiated with exogenous Ang II supplementation (non-dissection 14 related AAAs). One study unexpectedly reported no apparent influence of ACE2 deficiency on 15 AAA formation in the porcine pancreatic elastase intra-aortic infusion model 92 . This model 16 demonstrates greater pathologic fidelity to the human condition than aneurysms that develop 17 following focal aortic dissection in the Ang II infusion models. In a third modeling system, one 18 dependent on abluminal application of calcium chloride to initiate aneurysm formation, ACE2 19 deficiency was again found to augment experimental AAA formation, a similar response noted to 20 that demonstrated in the Ang II models (Table 1 & Fig. 1) ) 88 . 21

In the report describing the absence of AAA augmentation in ACE2 deficient mice 22

following PPE infusion, the magnitude of aneurysmal enlargement varied substantially in ACE2-23 deficient mice, thus the relatively small numbers of mice in each group may have increased the 1 risk for a type II error. In our own studies, conducted in elastase fusion model 100 , pretreatment 2 with Ang 1-7 suppressed, whereas pretreatment with a Mas receptor antagonist promoted, the 3 formation and progression of AAA-related pathologic changes (Table 1 & Fig. 1) . The initiation 4

of Ang 1-7 supplementation in mice following AAA initiation halted further enlargement, 5

suggesting a therapeutic application for Ang 1-7 or its analogues for clinical disease. 6

Additionally, treatment with a Mas receptor antagonist promoted further AAA expansion and 7

"rescuing" the AAA phenotype in mice treated with the AT1 blocker telmisartan, implying that 8 the demonstrated ability of telmisartan to suppress experimental AAA progression may be 9 dependent on Ang 1-7/Mas activity 11, 12 . 10

Altogether, while inconsistencies exist, the balance of experimental evidence suggests 11 that the ACE2-Ang 1-7-Mas axis exerts a regulatory role in AAA pathogenesis. The natural history of AAA disease is progressive aortic diameter enlargement over the 16 course of months to years to the point of symptomatic evolution or rupture. While intracranial 17 and coronary arterial aneurysms have developed in adults and children with COVID-19, 18 respectively ( Table 1) [101] [102] [103] [104] [105] [106] [107] , no similar relationship is yet recognized between SARS-CoV-2, 19 COVID-19, and AAA disease. However, several COVID-19-related mechanisms, either ACE2 20 dependent or independent, could impact AAA disease risk and progression currently and in the 21 years to come (Table 1, Fig. 1 & Fig. 2) . 22

As previously noted, coronaviruses, including SARS, SARS-CoV-2 and HCoV-NL63, 2 infect host cells via the binding of viral spike proteins to constitutively expressed ACE2 3

receptors. Viral spike protein endocytosis results in downregulation of cell surface ACE2 in 4 infected cells (Table 1 & Fig. 1 Fig. 1 ) 110, 111 . Both processes together reduce 6 cell surface expression of ACE2, critical for optimal catalytic activity (although soluble ACE2 7 also remains active). 8

During the SARS pandemic, SARS-CoV infection was associated with reduced cardiac 9 ACE2 protein levels in patients who succumbed to the disease 112 . Administration of human 10 SARS-CoV, or its surface spike protein, attenuates mRNA and protein levels of ACE2 in mouse 11 lung and heart tissue, with an increase in Ang II levels in the lung 112, 113 . Exposure of human lung 12 and kidney epithelial cells to SARS-CoV or its spike proteins also remarkably reduced ACE2 13 mRNA and protein expression 113, 114 . SARS-CoV spike protein alone was sufficient for 14 increasing pulmonary Ang II levels and promoting lung injury, although this effect could be 15 blocked by ARB treatment 113 . 16

In COVID-19 patients, plasma Ang II is elevated, whereas Ang 1-7 was reduced, 17 compared to healthy controls ( Alternatively, all vascular ECs, SMCs, pericytes, fibroblasts and certain immune cells 1 also express ACE2. Downregulation of ACE2 by SARS-CoV-2 on these cells will increase 2 vascular Ang II and AT1 activity. Shifting the Ang II/Ang 1-7 balance as a consequence of 3 SARS-CoV-2 infection may increase AAA risk or accelerate progression of early disease. To 4 better assess this risk, Ang II or Ang 1-7 production should be investigated in a large cohort of 5 active and convalescent COVID-19 patients. Binding of viral spike protein to ACE2 initiates the intracellular signaling cascade 9

promoting inflammatory mediator production. SARS-CoV proteins (including spike proteins) 10 augmented pro-aneurysmal chemokine CCL2 expression in human type II pneumocytes 118 . In 11 various tissues of SARS-CoV patients, expression of multiple mediators thought to promote 12 (CCL2, IL-1b, IL-6, TNF-a) and inhibit (TGF-b1) AAA disease progression were enhanced in 13 ACE2-positive cells 119 . In a recent single cell RNA analysis, CCL2 and CXCL12 were highly 14 enriched in ACE2-positive type II alveolar epithelial cells and arterial vascular cells from healthy 15 and diseased heart and lung as compared to ACE2-negative cells 38 with disease severity in VOD-19 patients [123] [124] [125] [126] . These findings suggest that SARS-CoV-2 10 infection may also enhance AAA pathogenesis by altering the production of proaneurysmal 11 mediators by ACE2-negative myeloid cells present in aneurysmal tissue (Table 1 & Fig. 2) . 

Severe COVID-19. medRxiv. 2020. Effects on/consequences of RAS dysregulation.

• ACE-Ang II-AT1 receptor activity promotes, whereas ACE2-Ang 1-7-Mas receptor activity inhibits, experimental AAAs • Reduced clinical AAA expansion associated with ARB use • ACE2 expression is reduced in aneurysmal aorta.

• Apelin and resveratrol, effective against experimental AAA, increases ACE2 expression.

• Circulating ACE2 inversely associated with AAA risk and operative mortality following repair. • Cell surface ACE2 internalization and shedding following SARS-CoV-2 entry impairs Ang II degradation and Ang 1-7 formation. • Increased Ang II and reduced Ang 1-7 serum levels in Covid-19 patients. J o u r n a l P r e -p r o o f • Participants: COVID-19 convalescent patients with or without AAAs 3, 6 and 12 months after hospital discharge as well as matched non-COVID-19 controls with or without AAAs • Approaches: Analyze plasma/serum. angiotensin II and angiotensin 1-7 via ELISA assays Are systemic levels of selected proaneurysmal mediators modified following COVID-19?

• Participants: COVID-19 convalescent patients with or without AAAs 3, 6 and 12 months after hospital discharge as well as matched non-COVID-19 controls with or without AAAs • Approaches: Proteomic or specific protein arrays to determine plasma/serum key proaneurysmal mediators such as IL-1β, IL-6, IL-17, TNF-α, CCL2, CCL5, MMP2, MMP9 and VEGF-A Is AAA enlargement rate, risk for rupture, or surgical repair at any given baseline aortic diameter increased following COVID-19?

• Participants: All AAA patients (regardless of COVID-19), or convalescent COVID-19 AAA patients and non-COVID-19 AAA patients. • Approaches: Compare AAA enlargement rate, rupture, or the need for surgical repair (primary endpoints) using retrospective casecontrol study, perform multi-variable analysis to determine whether COVID-19 is an independent factor for the development of a primary endpoint. Is aneurysm prevalence increased following COVID-19?

• Data source: Hospital electronic health record or Medicare database • Compare AAA prevalence before, during and after the COVID-19 pandemic period Does vaccination against SARS-CoV-2 modulate enlargement rate, risk for rupture or surgical repair of clinical AAAs? 

A crucial role of angiotensin 16 converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Airways Expression of SARS-CoV-2 Receptor, ACE2, and TMPRSS2 Is Lower 20 in Children Than Adults and Increases with Smoking and COPD

Clinical and biochemical 1 indexes from 2019-nCoV infected patients linked to viral loads and lung injury

COVID-19) is Associated with Low Circulating Plasma Levels of Angiotensin

Angiotensin 1,7

Elevation of plasma angiotensin II level is 7 a potential pathogenesis for the critically ill COVID-19 patients

Upregulation of the

C motif) ligand 2 via a severe acute respiratory syndrome coronavirus spike-10 ACE2 signaling pathway

Expression of elevated levels of 12 pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to 13 the acute lung injury and pathogenesis of SARS

SARS coronavirus spike protein-induced innate 15 immune response occurs via activation of the NF-kappaB pathway in human monocyte 16 macrophages in vitro

Up-regulation of IL-6 and TNF-alpha 18 induced by SARS-coronavirus spike protein in murine macrophages via NF-kappaB pathway

Severe acute respiratory syndrome 21 and the innate immune responses: modulation of effector cell function without productive 22 infection

Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with 2 COVID-19 severity in patients

Inflammasome activation by mitochondrial oxidative stress in macrophages leads to the 5 development of angiotensin II-induced aortic aneurysm

Oligomerization Domain-Like Receptor Family

Inflammasome Degrades Contractile Proteins: Implications for Aortic Biomechanical 10

Dysfunction and Aneurysm and Dissection Formation

Targeting the NLRP3

Inflammasome With Inhibitor MCC950 Prevents Aortic Aneurysms and Dissections in Mice

Severe acute respiratory syndrome 16 (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by 17 modulating intrinsic functions of monocyte-derived macrophages and dendritic cells

Host-Viral Infection Maps 20

Reveal Signatures of Severe COVID-19 Patients

Interferon Regulatory Factor 5 Promotes Experimental Abdominal Aortic Aneurysms

Receptor Deficiency Limits the Progression of Experimental Abdominal Aortic Aneurysms

Neutrophil Proteases

Promote Experimental Abdominal Aortic Aneurysm via Extracellular Trap Release and 8

Proteomic and Metabolomic 10 Characterization of COVID-19

Accumulation Is Associated with a Shift of Mitochondrial Respiratory Control and HIF-1α

Upregulation in PTEN Negative Prostate Cancer Cells

Hydroxyanthranilic Acid Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysm 16 Formation in Mice In Vivo

The preventive and 18 curative effects of melatonin against abdominal aortic aneurysm in rats

Protective effect of melatonin on 21 the development of abdominal aortic aneurysm in a rat model

SARS-CoV-2 vaccines in development