Clinical Implications of SARS-CoV-2 Interaction With Renin Angiotensin System: JACC Review Topic of the Week

Abstract

Severe acute respiratory-syndrome coronavirus-2 (SARS-CoV-2) host cell infection is mediated by binding to angiotensin-converting enzyme 2 (ACE2). Systemic dysregulation observed in SARS-CoV was previously postulated to be due to ACE2/angiotensin 1-7 (Ang1-7)/Mas axis downregulation; increased ACE2 activity was shown to mediate disease protection. Because angiotensin II receptor blockers, ACE inhibitors, and mineralocorticoid receptor antagonists increase ACE2 receptor expression, it has been tacitly believed that the use of these agents may facilitate viral disease; thus, they should not be used in high-risk patients with cardiovascular disease. Based on the anti-inflammatory benefits of the upregulation of the ACE2/Ang1-7/Mas axis and previously demonstrated benefits of lung function improvement in SARS-CoV infections, it has been hypothesized that the benefits of treatment with renin-angiotensin system inhibitors in SARS-CoV-2 may outweigh the risks and at the very least should not be withheld.

Keywords: ACE inhibitor; COVID-19; SARS-CoV-2; angiotensin II receptor blockers; angiotensin-converting enzyme-2; mineralocorticoid receptor antagonist.

Graphical abstract

Figure 1

RAS and ACE2/Ang1-7/Mas Axis Regulation Angiotensinogen is converted to angiotensin I (Ang I) via renin. Ang I is converted to Ang II via angiotensin-converting enzyme (ACE), which also hydrolyzes bradykinin into its inactive metabolites, promoting inflammation. The pro-inflammatory effects of Ang II are mediated by Ang II type I receptor (AT1), which stimulates aldosterone secretion from the adrenal medulla and antidiuretic hormone from the posterior pituitary. Aldosterone decreases membrane ACE2 expression. Endothelin-1 inhibits angiotensin 1-7 (Ang1-7) via extracellular signal-regulated kinase (ERK)1/ERK2 pathways. Ang II, under favorable conditions (dashed line), can be converted to Ang1-7 via ACE2, whose counter regulatory effects are mediated by the Mas receptor. Ang1-7 can also be formed via conversion of Ang I to an intermediate Ang1-9 or directly via zinc metallopeptidase neprilysin/prolyl endopeptidase (PEP). RAS = renin-angiotensin system.

Central Illustration

The Renin-Angiotensin System Interaction With COVID-19 Normally, angiotensin I (Ang I) is converted to Ang II via angiotensin-converting enzyme (ACE), which could be inhibited by ACE inhibitors. The pro-inflammatory effects of Ang II are mediated through AT1R in several ways: 1) in the zona glomerulosa of the adrenal medulla, it stimulates aldosterone secretion and binding to mineralocorticoid receptors to promote water reabsorption and to increase salt retention; it is inhibited by mineralocorticoid receptor antagonists (MRAs); 2) in the posterior pituitary, Ang II stimulates antidiuretic hormone secretion to promote water retention; and 3) in other tissues, it stimulates pathways responsible for hypertrophy, fibrosis, oxidative stress, and apoptosis. These effects are attenuated by angiotensin receptor blockers (ARBs), which block Ang II binding to AT1R. Ang II can also be converted to angiotensin 1-7 (Ang 1-7) via ACE2, which stimulates the Mas receptor promoting anti-inflammatory benefits. The ACE2/Ang1-7/Mas axis acts as a counter regulatory pathway to the traditional renin-angiotensin system (RAS). AT1R and ACE2 are coupled. Ang II binding to AT1R allows dissociation of ACE2 and subsequent degradation. ARB prevents dissociation of ACE2 and renders it availability for unused Ang II conversion to Ang 1-7. ACE2 has been identified as the targeted receptor for both the severe acute respiratory syndrome coronavirus (SARS-CoV) 2 and SARS-CoV. ACE2 mediates S protein binding that stimulates viral entry into the host cytosol that results in infection and viral replication. Diversion of Ang II towards ACE2 could competitively inhibit viral binding and also counter regulate the adverse effects caused by AT1R and improve outcomes by Mas R−based favorable effects.

Figure 2

Proposed Mechanism of Entry for SARS-CoV-2 Via ACE2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the catalytic site of ACE2 via its S protein. To gain access to the host cytosol, the S protein undergoes acid dependent proteolytic cleavage by ACE2, tumor necrosis factor (TNF)-α, transmembrane protease serine 2 (TMPRRS2), which results in the formation of an S1 and S2 subunit. S2 fusion peptide inserts into the membrane, which allows for clatherin-dependent endocytosis of ACE2-SARS-CoV-2. Viral binding stimulates TNF-α and calmodulin inhibitors to promote ectodomain cleavage of ACE2. ADAM 17 = disintegrin and metalloprotease 17; other abbreviations as in Figure 1.