SARS-CoV-2 infection and ACE2 expression in cardio-metabolic patients
ACE cleaves angiotensin (Ang) I to form Ang II within the renin-angiotensin system (RAS). Ang II has been recognized as the main active peptide that is cleaved by ACE2, a homolog of ACE, to form Ang-(1-7). ACE2 has high catalytic efficiency, suggesting an essential role in preventing Ang II accumulation, while enhancing Ang-(1-7) formation (Kalea & Batlle, 2010; Wysocki et al., 2010). ACE2 alterations have been described in experimental models of hypertension and diabetic kidney disease, and ACE2 levels were found to be decreased in the setting of hypertension (Mizuiri et al., 2008; Soler, Wysocki, Ye, Lloveras, Kanwar & Batlle, 2007; Wysocki et al., 2006; Ye, Wysocki, William, Soler, Cokic & Batlle, 2006). ACE2 expression is dramatically reduced with aging in both genders, young-adult vs. old (Xie, Chen, Wang, Zhang & Liu, 2006). Thus, ACE2 overexpression improves pancreatic islet-cell function, cardiovascular health, blood pressure, and renal protective arm of the RAS (Ferrario, 2006). ACE2 has a therapeutic effect for diabetes, cardiovascular conditions, kidney disease, and several other conditions in which the overactivity of Ang II is undesirable. Previous studies on SARS-CoV reported that the binding of viral S protein to ACE2 down-regulates the expression of ACE2, resulting in a diminished protective role of ACE2 and, subsequently, acute respiratory failure(Kuba et al., 2005). Downregulation or malfunction of ACE2 leads to accumulation of Ang II, resulting in a significant reduction in insulin secretion from the pancreas as well as glomerular filtration rate in the kidney (Batlle, Jose Soler & Ye, 2010).
Aging decreased expression of the ACE2 which also leads to accumulation of Ang II levels, in turn affecting other body organs like the heart, pancreas, and kidney. These factors suggest that treatment with ACE2 activating compounds could help to enhance hypertension and diabetic kidney disease during infection. However, the impact of ACE2 activators/inhibitors on the COVID-19 illness require urgent investigation. The current therapies should be continued at this point of COVID-19 illness as the withdrawing of the ARB therapies may not be wiser since there is no clinical evidence for the interaction of the ARB therapies and COVID-19 illness.
Based on current reports and pieces of evidence, we hypothesize that for the severe COVID-19 illness, drugs that activate the ACE2 function could help alleviate the reduced expression of ACE2 due to virus infection. For example, both Xanthenone and resorcinolnaphthalein were found to increase ACE2 activity in a dose-dependent manner. Xanthenone showed a remarkable antihypertensive effect, as it acutely decreased blood pressure by a massive 71 mmHg, however, its long-term antihypertensive effect was only moderate. Xanthenone was also found to improve cardiac function and reverse myocardial, perivascular, and renal fibrosis (Hernandez Prada et al., 2008). Additionally, a chemical compound, diminazene aceturate (DIZE), has been promoted as a potential ACE2 activator to treat ischemia-induced cardiac pathophysiology, pulmonary hypertension, and ischemic stroke (Qi et al., 2013). Wysocki et al. tested whether a soluble human recombinant ACE2 (rACE2) may be used to decrease ANG II and increase ANG (1–7) levels in plasma and tissues, and whether rACE2 may be used to prevent ANG II-induced hypertension in mice. Interestingly, this study found that rACE2 infusion induced a dose-dependent increase in serum ACE2 activity, but had no effect on kidney or cardiac ACE2 activity (Wysocki et al., 2010).