Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2

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.

Figure 1.

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 al; Page and Helmer). 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 al). The counter-regulatory axis of RAS was then described, pioneered with the discovery of ACE2 by 2 independent research groups (Donoghue et al; Tipnis et al) and identification of the Ang1–7/Mas receptor axis (Santos et al¹⁰¹). The cardioprotective effects of ACE2 were discovered shortly after (Crackower et al). Studies have identified the ACE2 protease domain as the receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV; Li et al) and, more recently, as the SARS-CoV-2 receptor (Walls et al; Yan et al).

Figure 2.

ACE2 (angiotensin-converting enzyme 2) expression throughout the body and schematic of ACE2 primary domains. A, ACE2 is expressed in the vascular system (endothelial cells, migratory angiogenic cells, and vascular smooth muscle cells), heart (cardiofibroblasts, cardiomyocytes, endothelial cells, pericytes, and epicardial adipose cells) and kidneys (glomerular endothelial cells, podocytes and proximal tubule epithelial cells). ACE2 is also expressed and functions in the local RAS of the liver (cholangiocytes and hepatocytes), retina (pigmented epithelial cells, rod and cone photoreceptor cells and Müller glial cells), enterocytes of the intestines, circumventricular organs of the central nervous system, upper airway (goblet and ciliated epithelial cells), and alveolar (Type II) epithelial cells of the lungs and pulmonary vasculature. B, ACE2 has an extracellular facing N-terminal domain and a C-terminal transmembrane domain with a cytosolic tail. The N-terminal portion of the protein contains the claw-like protease domain (PD), while the C-terminal domain is referred to as the Collectrin-like domain. The receptor-binding domain (RBD) of severe acute respiratory syndrome-coronavirus (SARS-CoV-2) binds with the PD of ACE2, forming the RBD-PD complex distinct from the ACE2 catalytic site.

Figure 3.

Role of ACE2 (angiotensin-converting enzyme 2) in the pathogenesis of coronavirus disease 2019 and the inflammatory response. ACE2-mediated cardiovascular protection is lost following endocytosis of the enzyme along with severe acute respiratory syndrome-coronavirus (SARS-CoV-2) viral particles. Ang II (angiotensin II) levels elevate with increased activity of angiotensin 1 receptors (AT₁R) at the cost of ACE2/Ang 1–7 driven pathways leading to adverse fibrosis, hypertrophy, increased reactive oxygen species (ROS), vasoconstriction, and gut dysbiosis. ADAM17 (a disintegrin and metalloproteinase 17)-mediated proteolytic cleavage of ACE2 is upregulated by endocytosed SARS-CoV-2 spike proteins. Activation of the AT₁R by elevated Ang II levels also further increases ADAM17 activity. ADAM17 correspondingly also cleaves its primary substrate releasing soluble TNF-α (tumor necrosis factor-α) into the extracellular region where it has auto- and paracrine functionality. TNF-α activation of its tumor necrosis factor receptor (TNFR) represents a third pathway elevating ADAM17 activity. TNF-α along with systemic cytokines released due to SARS-CoV-2 infection and in conjunction with comorbidities such as diabetes mellitus and hypertension can lead to a cytokine storm. TMPRSS2 indicates transmembrane protease serine 2.

Figure 4.

Link between ACE2 (angiotensin converting enzyme 2), gut dysbiosis, and cardiovascular disease. Loss of ACE2 on the luminal surface of the gut alters microbiota profiles facilitating dysbiosis and disruption of the integrity of the epithelial barrier. Epithelial dysfunction provides a conduit for both gastrointestinal metabolites and bacterium passage into the vascular bed driving local and systemic inflammation, which may cumulate in hypertension and septic shock. ACE2 deficiency and gut dysbiosis predisposes to the development of pulmonary hypertension through the gut-lung axis. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) enteric or pulmonary infection can further worsen the pathophysiology of the gut-lung axis through increased bacterial infiltration and inflammation in addition to worsened pulmonary function. AT1R indicates angiotensin II type 1 receptor; and COVID-19, coronavirus disease 2019.

Figure 5.

ACE2 (angiotensin converting enzyme 2) role in the renin-angiotensin system peptide cascade and its interaction with the apelinergic peptide system. A, Angiotensinogen is processed by renin into Ang I (angiotensin I), which is further cleaved by ACE or mast cell chymase into Ang II. Ang II can go on to affect the cardiovascular system predominantly through the angiotensin type 1 receptor (AT₁R) or via the angiotensin type 2 receptor (AT₂R). Alternatively, Ang II can be degraded by the carboxypeptidase ACE2 or the PCP (prolyl carboxypeptidase) into Ang 1–7 (angiotensin 1–7). Ang 1–7 mediates protective effects throughout tissues which host the Mas receptor (MasR). Ang 1–7 can be further formed through the activity of ACE2 on Ang I forming Ang 1-9 which is then cleaved by either ACE or NEP (neprilysin). B, Stimulation of the apelin receptor by apelin peptides leads to cardiovascular protective effects while disrupting Ang II signaling by sequestration of the AT₁R through receptor heterodimerization. Apelin is inactivated by ACE2 cleavage of its C-terminal phenylalanine while stimulation of the apelin receptor promotes ACE2 mRNA transcription presenting apelin’s role as a positive regulator of ACE2. ROS indicates reactive oxygen species.

Figure 6.

Loss of ACE2 (angiotensin converting enzyme 2) exacerbates diabetic cardiovascular complications via a multitude of disease mechanisms. The loss of ACE2 action in diabetic states elevates Ang II (angiotensin II) and lowers Ang 1–7 levels in tissues and systemically. Increased Ang II/angiotensin II type 1 receptor (AT₁R) signaling drives multiple pathologies in various end-organs elevating reactive oxygen species (ROS) and promoting fibrosis, hypertrophy, and inflammation aggravated by the loss of the protective effects of Ang 1–7. Ang II stimulation also systemically alters metabolic profiles and modulates insulin sensitivity in affected tissues.