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Celebrating 20th Anniversary of ACE2

Discovery Overlaps with COVID-19 Hijacking ACE2 (an insightful overview)

Circ Res. 2020 May 8;126(10):1456-1474. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Gheblawi M#1,2, Wang K#3,2, Viveiros A1,2, Nguyen Q3,2, Zhong JC4, Turner AJ5, Raizada MK6, Grant MB7, Oudit GY1,3,2. Author information 1 From the Department of Physiology (M.G., A.V., G.Y.O.). 2 Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada (M.G., K.W., A.V., Q.N., G.Y.O.). 3 Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada (K.W., Q.N., G.Y.O.). 4 Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, China (J.-C.Z.). 5 School of Biomedical Sciences, University of Leeds, United Kingdom (A.J.T.). 6 Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (M.K.R.). 7 Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham (M.B.G.). Abstract ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1-7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases. KEYWORDS: cardiovascular diseases; coronavirus; dysbiosis; heart failure; renin-angiotensin system

Historical timeline of discovery of the major renin-angiotensin system (RAS) components, including ACE2 (angiotensin-converting enzyme 2). Renin was the first component of the RAS discovered following the finding that extracts from rabbit kidney produced pressor effects (Tigerstedt and Bergman, 1898). Constriction of the renal artery was then found to lead to hypertension (HTN), thus driving the discovery of hypertensin and angiotonin (and later termed angiotensin; Goldblatt et al27; Page and Helmer24). Ang (angiotensin) was subsequently purified, and 2 forms were resolved: Ang I and Ang II. Therefore, the existence of a converting enzyme was predicted (ACE) and subsequently isolated and characterized (Skeggs et al26). The counter-regulatory axis of RAS was then described, pioneered with the discovery of ACE2 by 2 independent research groups (Donoghue et al3; Tipnis et al2) and identification of the Ang1–7/Mas receptor axis (Santos et al101). The cardioprotective effects of ACE2 were discovered shortly after (Crackower et al25). Studies have identified the ACE2 protease domain as the receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV; Li et al5) and, more recently, as the SARS-CoV-2 receptor (Walls et al15; Yan et al16).

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