ACE2, Much More Than Just a Receptor for SARS-COV-2

Abstract

The rapidly evolving pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection worldwide cost many lives. The angiotensin converting enzyme-2 (ACE-2) has been identified as the receptor for the SARS-CoV-2 viral entry. As such, it is now receiving renewed attention as a potential target for anti-viral therapeutics. We review the physiological functions of ACE2 in the cardiovascular system and the lungs, and how the activation of ACE2/MAS/G protein coupled receptor contributes in reducing acute injury and inhibiting fibrogenesis of the lungs and protecting the cardiovascular system. In this perspective, we predominantly focus on the impact of SARS-CoV-2 infection on ACE2 and dysregulation of the protective effect of ACE2/MAS/G protein pathway vs. the deleterious effect of Renin/Angiotensin/Aldosterone. We discuss the potential effect of invasion of SARS-CoV-2 on the function of ACE2 and the loss of the protective effect of the ACE2/MAS pathway in alveolar epithelial cells and how this may amplify systemic deleterious effect of renin-angiotensin aldosterone system (RAS) in the host. Furthermore, we speculate the potential of exploiting the modulation of ACE2/MAS pathway as a natural protection of lung injury by modulation of ACE2/MAS axis or by developing targeted drugs to inhibit proteases required for viral entry.

Keywords: COVID-19; alveolar; angiotensin; coagulopathy; lung.

Figure 1

Dysregulation of Ang II and Ang (1-7) by loss of protective function of ACE2 receptor. (A) under physiological condition there is a balance in ACE and ACE2 receptor activity. ACE regulates the Renin Angiotensin Aldosterone system (RAS) and cleaves Ang I to produce Ang II. Ang II is a potent vasoconstrictor and detrimental for endothelial and epithelial function through activating AT1 and AT2 receptors. The counterbalance of the RAS/Ang II output is regulated by ACE2 and Mas/G protein coupled receptor activity. ACE2 cleaves Ang I and Ang II into Ang-1-9 and Ang1-7, respectively, thereby it activates MAS/G protein coupled receptor that protect cell death. (B) SARS-CoV-2 binds to ACE2 to gain entry to epithelial cells of the lungs. Cleavage of spike proteins by a protease such as trypsin/cathepsin G and or ADAM17 on ectodomain and TMPRSS2 of endodomain sites facilitate viral entry into the cells. This process leads to shedding of host ACE2 receptors and loss of its protective function. Loss of function of ACE2 activity prevents production of Ang 1-9 and Ang1-7. Lack of Ang1-7 diminishes the activity of MAS/G receptor, leading to the loss of its protective functions including vasodilatation, cell protection both at the epithelial and endothelial sites. Loss of ACE2 function leads to an imbalance and unchecked effects of Ang II and upregulation of RAS/Ang II pathway. Upregulation of Ang II leads to vasoconstriction, thrombophilia, microthrombosis, alveolar epithelial injury and respiratory failure. Therefore, inhibiting the proteolytic function of trypsin/cathepsin and ADAM17 or TMPRSS2 and or direct activation of MAS/G receptor by enhancing Ang-(1-7) can overcome the loss of function ACE2 and are viable targets to prevent tissue damage to the host.