Angiotensin-Converting Enzyme 2 Expression and Severity of SARS-CoV-2 Infection

Abstract

Angiotensin-converting enzyme 2 (ACE2), first discovered in 2000, serves as an important counterregulatory enzyme to the angiotensin II-mediated vasoconstrictive, pro-inflammatory, and pro-fibrotic actions of the renin-angiotensin system (RAS). Conversion of angiotensin II to the peptide angiotensin 1-7 (ANG 1-7) exerts protective vasodilatory, anti-inflammatory, and anti-fibrotic actions through interaction with the MasR receptor. There are many important considerations when noting the role of ACE2 in the pathogenesis and sequelae of COVID-19 infection. ACE2, in the role of COVID-19 infection, was recognized early in 2020 at the beginning of the pandemic as a cell membrane-bound and soluble binding site for the viral spike protein facilitating entering into tissue cells expressing ACE2, such as the lungs, heart, gut, and kidneys. Mechanisms exist that alter the magnitude of circulating and membrane-bound ACE2 (e.g., SARS-CoV-2 infection, viral variants, patient characteristics, chronic disease states, and the degree of cell surface expression of ACE2) and the influence these mechanisms have on the severity of disease and associated complications (e.g., respiratory failure, systemic inflammatory response syndrome, acute myocarditis, acute kidney injury). Several medications alter the ACE2 receptor expression, but whether these medications can influence the course of the disease and improve outcomes is unclear. In this review, we will discuss what is known about the interrelation of SARS-CoV-2, ACE2 and the factors that may contribute to the variability of its expression and potential contributors to the severity of COVID-19 infection.

Keywords: COVID-19; SARS-CoV-2; angiotensin-converting enzyme 2.

Figure 1

Angiotensin-converting enzyme 2 (ACE2) functions by converting Angiotensin 1 (Ang I) and Angiotensin 2 (Ang II) to Angiotensin 1–9 (Ang 1–9) and Angiotensin 1–7 (Ang 1–7), respectively. Ang 1–9 can further be converted to Ang 1–7; Ang 1–7 acts at the MAS1 oncogene (MasR). Ang II can act directly at the Angiotensin Receptor Type 1 (AT1R) or be converted into Angiotensin III (ANG III) by aminopeptidase (APA), which can act at both AT1R or Angiotensin Receptor Type 2 (AT2R). AT1R functions to increase vasoconstriction, fibrosis, hypertrophy, and inflammation, whereas MasR opposes each of these effects. The increased presence of ACE2 catalyzes the shift from Ang II-mediated processes toward those mediated by Ang 1–7, thus influencing the balance in these opposing forces.