Angiotensin Converting Enzyme 2
Authors: Kaiming Wang, Mahmoud Gheblawi, Gavin Y. Oudit
Journal: Circulation (2020)

ngiotensin converting enzyme 2 (ACE2) has garnered much attention given the current coronavirus disease 2019 (COVID-19) pandemic as the cellular receptor for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).ACE2 was discovered 20 years ago based on approaches searching for ACE homologues and was initially cloned from human heart failure ventricular and lymphoma cDNA libraries. 1Since then, 2 major functions have been identified for ACE2: (1) an endogenous counter-regulator of the renin-angiotensin system (RAS), and (2) a cellular receptor for SARS-CoV and SARS-CoV-2 viruses.ACE2 is ubiquitously expressed with highest levels detected in the cardiovascular system, gut, kidneys, and lungs.In the cardiovascular system, ACE2 is expressed in cardiomyocytes, epicardial adipose tissue, cardiac fibroblasts, vascular smooth muscle, and endothelial cells. 1,2ACE2 is a type I transmembrane protein that functions as a monocarboxypeptidase with a catalytically active ectodomain exposed to the circulation that hydrolyzes various peptides, including angiotensin II and angiotensin I, generating angiotensin 1-7 and angiotensin 1-9, respectively. 1A soluble form of ACE2 can be released from the membrane through proteolytic cleavage mediated by ADAM17 (ADAM metallopeptidase domain 17) resulting in loss of ACE2 protection against tissue RAS and increased plasma ACE2 activity, a known marker of adverse prognosis in patients with cardiovascular disease.The discovery of ACE2 introduced an alternative protective arm, ACE2/angiotensin 1-7/Mas receptor axis, to counterbalance the more renowned pathogenic ACE/ angiotensin II/angiotensin II receptor type 1 (AT 1 ) receptor axis that predominates in disease states as a result of RAS overactivation (Figure A).Cleavage of angiotensin I by ACE generates angiotensin II, which is the primary effector peptide of the ACE/ angiotensin II/AT 1 receptor axis, triggering potent vasoconstriction, inflammation, cell proliferation, hypertrophy, fibrosis, and tissue remodeling.ACE2 cleaves angiotensin II into the cardioprotective angiotensin 1-7, which acts through Mas receptors to counterbalance the detrimental effects of angiotensin II signaling.Therefore, ACE2 protects against RAS-induced injuries through 2 processes: (1) degrading angiotensin I and angiotensin II to limit substrate availability in the adverse ACE/angiotensin II/AT 1 receptor axis, and (2) generating angiotensin 1-7 to increase substrate availability in the protective ACE2/angiotensin 1-7/Mas receptor axis.Loss-of-function experiments using ACE2 knockout mice and ACE2 inhibitors have revealed increased susceptibility to myocardial infarction, hypertension, and angiotensin II-induced myocardial hypertrophy, microvascular complications, inflammation, fibrosis, diastolic and systolic dysfunction, and oxidative stress. 1,2Importantly, partial loss of ACE2, as seen in human hearts explanted from patients with heart failure and dilated cardiomyopathy, is sufficient to enhance the susceptibility to heart disease. 1 Conversely, gain-of-function experiments with recombinant ACE2, overexpression of ACE2, and supplemental angiotensin 1-7 have shown protective roles in various models of cardiovascular disease including hypertension,