COVID-19, ACE2, and the cardiovascular consequences

Abstract

The novel SARS coronavirus SARS-CoV-2 pandemic may be particularly deleterious to patients with underlying cardiovascular disease (CVD). The mechanism for SARS-CoV-2 infection is the requisite binding of the virus to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) and internalization of the complex by the host cell. Recognition that ACE2 is the coreceptor for the coronavirus has prompted new therapeutic approaches to block the enzyme or reduce its expression to prevent the cellular entry and SARS-CoV-2 infection in tissues that express ACE2 including lung, heart, kidney, brain, and gut. ACE2, however, is a key enzymatic component of the renin-angiotensin-aldosterone system (RAAS); ACE2 degrades ANG II, a peptide with multiple actions that promote CVD, and generates Ang-(1-7), which antagonizes the effects of ANG II. Moreover, experimental evidence suggests that RAAS blockade by ACE inhibitors, ANG II type 1 receptor antagonists, and mineralocorticoid antagonists, as well as statins, enhance ACE2 which, in part, contributes to the benefit of these regimens. In lieu of the fact that many older patients with hypertension or other CVDs are routinely treated with RAAS blockers and statins, new clinical concerns have developed regarding whether these patients are at greater risk for SARS-CoV-2 infection, whether RAAS and statin therapy should be discontinued, and the potential consequences of RAAS blockade to COVID-19-related pathologies such as acute and chronic respiratory disease. The current perspective critically examines the evidence for ACE2 regulation by RAAS blockade and statins, the cardiovascular benefits of ACE2, and whether ACE2 blockade is a viable approach to attenuate COVID-19.

Keywords: ACE2; ANG II; COVID-19; SARS-CoV-2; renin-angiotensin system; statins.

Fig. 1.

Processing and functional scheme of the renin-angiotensin system. The protease renin converts the precursor angiotensinogen to angiotensin I (ANG I), which is subsequently converted to ANG II by dipeptidyl carboxypeptidase angiotensin-converting enzyme (ACE). ANG II binds to the ANG II type 1 receptor (AT₁R) to stimulate inflammation, fibrosis, oxidative stress, and an increase in blood pressure. ANG II is metabolized to ANG III and ANG IV through various aminopeptidases (APs). ANG I and ANG II are converted to Ang-(1–7) via endopeptidases (NEP) and the monocarboxypeptidase ACE2, respectively. Ang-(1–7) binds to the Mas receptor (Mas-R) to exert anti-inflammatory and antifibrotic actions, stimulate the release of nitric oxide, and reduce blood pressure. Ang-(1–7) is metabolized to Ang-(1–5) by ACE. Major forming and degrading pathways are depicted by solid and dashed lines, respectively. SARS-CoV-2 binds to ACE2 to stimulate internalization of both the virus and peptidase that may remove ACE2 from this pathway.

Fig. 2.

Influence of angiotensin II (ANG II) type 1 receptor or angiotensin-converting enzyme (ACE) blockade on ACE2 activity in the heart and kidney of normotensive Lewis and hypertensive mRen2.Lewis rats. Chronic blockade with losartan (LOS) increased cardiac ACE2 activity by 3-fold in normotensive Lewis and 2-fold hypertensive mRen2.Lewis (mRen2) male rats. Lisinopril (LIS) treatment had little or no effect on cardiac ACE2 activity in these strains. Chronic LOS or LIS treatment increased renal ACE2 activity in the Lewis (1.3- and 1.7-fold, respectively) and mRen2 (1.3- and 1.2-fold, respectively). ACE2 activity is the amount of Ang-(1–7) converted from ANG II in the plasma membrane fraction (fmol Ang-(1–7)·mg protein⁻¹·min⁻¹) sensitive to the ACE2 inhibitor MLN4760 (3). Data are means ± SE; n = 6–8. *P < 0.05 (10, 11, 22). CON, control.