Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System

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.

ACE2 polymorphisms and individual susceptibility to SARS-CoV-2 infection: insights from anin silicostudy

“…On the other hand, it has been hypothesized that, regardless of sex, pharmacological (antihypertensive drugs, such as ACE inhibitors and sartans) or environmental factors (NO2 pollution), capable of inducing an overexpression of ACE2 could be responsible of increased susceptibility to infection and/or greater severity 47 . ACE2 plays an essential role in the renin-angiotensinaldosterone system, and its loss of function due to the massive binding of viral particles and internalization could constitute an essential element of the pathophysiology of pulmonary and cardiac damage during COVID-19 infection 47,48 . In this context it should be underlined that ACE2…”

Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence

“…To access host cells, SARS-CoV-2 uses a surface glycoprotein (peplomer) known as spike; ACE2 has been shown to be a co-receptor for coronavirus entry [28][29][30]. Therefore, the density of ACE2 in each tissue may correlate with the severity of the disease in that tissue [31][32][33][34][35][36]. Other receptors on the surface of human cells have been suggested to mediate the entry of SARS-CoV-2 [5], including transmembrane serine protease 2 (TMPRSS2) [37,38], sialic acid receptors [39,40], and extracellular matrix metalloproteinase inducer (CD147, also known as basigin) [41].…”

Renin-angiotensin system at the heart of COVID-19 pandemic

“…In animal models, the loss of ACE2 resulted in increased production of reactive oxygen species (ROS) via NADPH oxidase 2 activation, and administration of recombinant ACE2 was shown to inhibit the angiotensin II effects on TGF-β1 activation and collagen production [14]. Recombinant ACE2 pulmonary overexpression attenuates whole aspects of pulmonary artery hypertension pathophysiology [23], suggesting that its loss of function (as could occur in case of massive binding by viral particles, with subsequent endocytosis and activation of proteolytic cleavage [24]) could participate in the severity of respiratory distress. More importantly, loss of function of ACE2 cannot counterbalance the deleterious effects of Angiotensin II in promoting degradation of cardiac and lung structures and function [24].…”

“…Recombinant ACE2 pulmonary overexpression attenuates whole aspects of pulmonary artery hypertension pathophysiology [23], suggesting that its loss of function (as could occur in case of massive binding by viral particles, with subsequent endocytosis and activation of proteolytic cleavage [24]) could participate in the severity of respiratory distress. More importantly, loss of function of ACE2 cannot counterbalance the deleterious effects of Angiotensin II in promoting degradation of cardiac and lung structures and function [24]. Thus, angiotensin II receptor blockers could also potentially exert a protective action in the late phases of SARS COVID-19 by counteracting the negative effects of Angiotensin II.…”