A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

Abstract

The recent emergence of coronavirus disease-2019 (COVID-19) as a global pandemic has prompted scientists to address an urgent need for defining mechanisms of disease pathology and treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, employs angiotensin converting enzyme 2 (ACE2) as its primary target for cell surface attachment and likely entry into the host cell. Thus, understanding factors that may regulate the expression and function of ACE2 in the healthy and diseased body is critical for clinical intervention. Over 66% of all adults in the United States are currently using a prescription drug and while earlier findings have focused on possible upregulation of ACE2 expression through the use of renin angiotensin system (RAS) inhibitors, mounting evidence suggests that various other widely administered drugs used in the treatment of hypertension, heart failure, diabetes mellitus, hyperlipidemias, coagulation disorders, and pulmonary disease may also present a varied risk for COVID-19. Specifically, we summarize mechanisms on how heparin, statins, steroids and phytochemicals, besides their established therapeutic effects, may also interfere with SARS-CoV-2 viral entry into cells. We also describe evidence on the effect of several vitamins, phytochemicals, and naturally occurring compounds on ACE2 expression and activity in various tissues and disease models. This comprehensive review aims to provide a timely compendium on the potential impact of commonly prescribed drugs and pharmacologically active compounds on COVID-19 pathology and risk through regulation of ACE2 and RAS signaling.

Colonic Epithelial Angiotensin-Converting Enzyme 2 (ACE2) Expression in Blacks and Whites: Potential Implications for Pathogenesis Covid-19 Racial Disparities

“…Other limitations include the modest sample size which precluded univariable (p = 0.07) analysis achieving statistical significance, but the multivariable analysis is reassuring. Other putative confounders such as hypertension or medications which may modulate ACE2 expression (e.g., ARBs have been shown to increase cardiac ACE2 levels) were unable to be assessed [24]. In addition, the relative importance of these biological factors versus socioeconomic remains to be determined [25].…”

Current Updates on Naturally Occurring Compounds Recognizing SARS-CoV-2 Druggable Targets

“…Conversely, a computational investigation evidenced it as able to bind at S protein: ACE2 receptor interface [73]. In vitro studies demonstrated that quercetin inhibited recombinant human (rh) ACE2 activity [74,75]. More recently, the clinical trials (NCT04468139 and NCT04377789) including quercetin, were involved in both prophylaxis and treatment of COVID-19 [76][77][78].…”

Heart Failure and Coronavirus Disease-19

“…The proteins together with viral RNA are assembled to form new viruses and released from host cell through exocytosis. This process results in host cell damage and invasion of new cells [16], [18], [19]. Viral invasion also downregulates the ACE2 and stimulates reninangiotensin-aldosterone system activation which promotes organ specific injury [19].…”

“…ACE-2 is present in alveolar epithelial cells, enterocytes, vascular endothelial cells, and cardiac myocytes and pericytes. This causes the presence of cardiovascular manifestations in COVID-19 [18], [21]. Direct effect of viral invasion causes damage to myocytes and pericytes.…”