The Controversy of Renin-Angiotensin-System Blocker Facilitation Versus Countering COVID-19 Infection.

Manolis, Antonis S; Manolis, Theodora A; Manolis, Antonis A; Melita, Helen

The ongoing COVID-19 pandemic has produced serious turmoil world-wide. Lung injury causing acute respiratory distress syndrome (ARDS) appears to be a most dreaded complication occurring in ∼30%. Older patients with cardiovascular (CV) comorbidities and ARDS have an increased mortality. Although the precise mechanisms involved in the development of lung injury have not been fully elucidated, the role of the extended renin-angiotensin system (RAS) appears to be pivotal. In this context, angiotensin-converting enzyme 2 (ACE2), an ACE homologue, has been recognized as a facilitator of viral entry into the host, albeit its involvement in other counter-regulatory effects, such as converting angiotensin (Ang) II into Ang 1-7 with its known protective actions. Thus, concern was raised that the use of RAS inhibitors by increasing ACE2 expression may enhance patient susceptibility to the COVID virus. However, current data have appeased such concerns as there has been no clinical evidence of a harmful effect of these agents as based on observational studies. However, properly designed future studies will be needed to further confirm or refute current evidence. Furthermore, other pathways may also play important roles in COVID-19 transmission and pathogenesis; spike (S) protein proteases facilitate viral transmission by cleaving S protein that promotes viral entry into the host; neprilysin (NEP), a neutral endopeptidase known to cleave natriuretic peptides, degrades Ang I into Ang 1-7; NEP can also catabolize bradykinin and thus mitigate bradykinin's role in inflammation, while, in the same context, specific bradykinin inhibitors might also negate bradykinin's harmful effects. Based on these intricate mechanisms, various preventive and therapeutic strategies may be devised, such as upregulating ACE2 and/or using recombinant ACE2, and exploiting the NEP, bradykinin and serine protease pathways, in addition to anti-inflammatory and antiviral therapies. These issues are herein reviewed, available studies are tabulated and pathogenetic mechanisms are pictorially illustrated.