Correcting the imbalanced protective RAS in COVID-19 with angiotensin AT2-receptor agonists.

U Muscha Steckelings,Colin Sumners

doi:10.1042/cs20200922

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the global corona virus disease 2019 (COVID-19) pandemic enters host cells via a mechanism that includes binding to angiotensin converting enzyme (ACE) 2 (ACE2). Membrane-bound ACE2 is depleted as a result of this entry mechanism. The consequence is that the protective renin-angiotensin system (RAS), of which ACE2 is an essential component, is compromised through lack of production of the protective peptides angiotensin-(1-7) and angiotensin-(1-9), and therefore decreased stimulation of Mas (receptor Mas) and angiotensin AT2-receptors (AT2Rs), while angiotensin AT1-receptors (AT1Rs) are overstimulated due to less degradation of angiotensin II (Ang II) by ACE2. The protective RAS has numerous beneficial actions, including anti-inflammatory, anti-coagulative, anti-fibrotic effects along with endothelial and neural protection; opposite to the deleterious effects caused by heightened stimulation of angiotensin AT1R. Given that patients with severe COVID-19 exhibit an excessive immune response, endothelial dysfunction, increased clotting, thromboses and stroke, enhancing the activity of the protective RAS is likely beneficial. In this article, we discuss the evidence for a dysfunctional protective RAS in COVID and develop a rationale that the protective RAS imbalance in COVID-19 may be corrected by using AT2R agonists. We further review preclinical studies with AT2R agonists which suggest that AT2R stimulation may be therapeutically effective to treat COVID-19-induced disorders of various organ systems such as lung, vasculature, or the brain. Finally, we provide information on the design of a clinical trial in which patients with COVID-19 were treated with the AT2R agonist Compound 21 (C21). This trial has been completed, but results have not yet been reported.

Highlights

The discovery in 2003 of angiotensin converting enzyme (ACE) 2 (ACE2) as the binding site and cellular entry point for the severe acute respiratory syndrome coronavirus (SARS-CoV) unexpectedly pointed to a link between coronavirus infections and the renin–angiotensin system (RAS) [1]
The COVID-19 pandemic that is a result of infection with the SARS-CoV-2 coronavirus is affecting millions of people and the death toll has exceeded 1.3 million victims
Scientists all over the world are trying to develop vaccines and effective treatments to bring down the number of COVID-19 associated fatalities and severe courses of disease and to get us all back to a life with normal social interactions and daily routines

Summary

Introduction

The discovery in 2003 of angiotensin converting enzyme (ACE) 2 (ACE2) as the binding site and cellular entry point for the severe acute respiratory syndrome coronavirus (SARS-CoV) unexpectedly pointed to a link between coronavirus infections and the renin–angiotensin system (RAS) [1]. As discussed in the preceding sections, infection of a cell or organism with a SARS-CoV virus leads to a reduction in ACE2 enzymatic activity, resulting in a lessening of the synthesis of the protective RAS mediators Ang-(1-7) and Ang-(1-9) and, subsequently, decreased stimulation of the receptor Mas and the AT2R [11]. A number of recent clinical studies have indicated beneficial effects of corticosteroids administered systemically to patients with ARDS in severe COVID-19 disease [71] It is well-known that AT2R agonists exert powerful anti-inflammatory actions [72,73,74,75]; they may be prime candidates to compensate for the loss of ACE2/Ang-(1-7) protective mechanisms and help offset the large pro-inflammatory response in COVID-19 patients with severe disease (Figure 2).

Conclusions

Ethics Approval