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.

Ursodeoxycholic acid does not affect the clinical outcome of SARS‐CoV‐2 infection: A retrospective study of propensity score‐matched cohorts

“…Based on the previously mentioned principles, therapies that modulate ACE2 expression might be also successful against different variants of SARS-CoV2 with a higher genetic barrier to resistance than vaccines and monoclonal antibodies. 12 In a recently published study, Brevini et al 13 identified the farnesoid X receptor (FXR) as a regulator of ACE2 expression in multiple COVID-19-affected tissues, including the gastrointestinal and respiratory systems. These authors found that FXR antagonists, including the over-the-counter compound z-guggulsterone (ZGG) and the off- UDCA is a hydrophilic bile acid that has been approved by the US Food and Drug Administration (FDA) for dissolving gallstones and for the treatment of several cholestatic liver diseases, such as primary biliary cholangitis.…”

“…On these principles vaccines and monoclonal antibodies have been introduced in clinical practice. Based on the previously mentioned principles, therapies that modulate ACE2 expression might be also successful against different variants of SARS‐CoV2 with a higher genetic barrier to resistance than vaccines and monoclonal antibodies 12 …”

Inclusion of deuterated glycopeptides provides increased sequence coverage in hydrogen/deuterium exchange mass spectrometry analysis of SARS‐CoV‐2 spike glycoprotein

“…Spike is a trimeric surface glycoprotein from the SARS‐CoV‐2 virus causing the COVID‐19 pandemic 1,2 . Spike's binding to human angiotensin‐converting enzyme 2 (ACE2) is critical for SARS‐CoV‐2 penetration of a host cell and initiation of infection 3–5 . Spike is the surface antigen and target of all currently available COVID‐19 vaccines, 6 and improved understanding of spike's structures and functions is likely to result in more effective SARS‐CoV‐2 vaccines 7 …”

“…1,2 Spike's binding to human angiotensin-converting enzyme 2 (ACE2) is critical for SARS-CoV-2 penetration of a host cell and initiation of infection. [3][4][5] Spike is the surface antigen and target of all currently available COVID-19 vaccines, 6 and improved understanding of spike's structures and functions is likely to result in more effective SARS-CoV-2 vaccines. 7 Spike trimers engage in several dynamic structural changes related to binding ACE2, cleavage by protease TMPRSS2, unfolding their S2 domains, and finally refolding to pull viral and target cell membranes into juxtaposition.…”

Inclusion of deuterated glycopeptides provides increased sequence coverage in hydrogen/deuterium exchange mass spectrometry analysis of SARS-CoV-2 spike glycoprotein

“…Spike is a trimeric surface glycoprotein from the SARS-CoV-2 virus causing the COVID-19 pandemic (1, 2). Spike's binding to human angiotensin-converting enzyme 2 (ACE2) is critical for SARS-CoV-2 penetration of a host cell and initiation of infection (3,4,5). Spike is the surface antigen and target of all currently available COVID-19 vaccines (6), and improved understanding of spike's structures and functions is likely to result in more effective SARS-CoV-2 vaccines (7).…”