Renin-Angiotensin System and Sex Differences in COVID-19: A Critical Assessment

• Published in: Circulation research Vol. 132; no. 10; pp. 1320 - 1337
• Main Author: Chappell, Mark C.
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 12.05.2023
• Subjects: Angiotensin-Converting Enzyme 2 - metabolism; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Compendium on COVID-19 and Cardiovascular Disease; COVID-19; Female; Humans; Male; Peptidyl-Dipeptidase A - physiology; Post-Acute COVID-19 Syndrome; Renin-Angiotensin System - physiology; SARS-CoV-2; Sex Characteristics; SARS-CoV-2; androgen; estrogen; peptidyl-dipeptidase A; angiotensin-converting enzyme 2; renin-angiotensin system
• DOI: 10.1161/CIRCRESAHA.123.321883
• ISSN: 0009-7330; 1524-4571

The current epidemic of corona virus disease (COVID-19) has resulted in an immense health burden that became the third leading cause of death and potentially contributed to a decline in life expectancy in the United States. The severe acute respiratory syndrome-related coronavirus-2 binds to the surface-bound peptidase angiotensin-converting enzyme 2 (ACE2, EC 3.4.17.23) leading to tissue infection and viral replication. ACE2 is an important enzymatic component of the renin-angiotensin system (RAS) expressed in the lung and other organs. The peptidase regulates the levels of the peptide hormones Ang II and Ang-(1–7), which have distinct and opposing actions to one another, as well as other cardiovascular peptides. A potential consequence of severe acute respiratory syndrome-related coronavirus-2 infection is reduced ACE2 activity by internalization of the viral-ACE2 complex and subsequent activation of the RAS (higher ratio of Ang II:Ang-[1–7]) that may exacerbate the acute inflammatory events in COVID-19 patients and possibly contribute to the effects of long COVID-19. Moreover, COVID-19 patients present with an array of autoantibodies to various components of the RAS including the peptide Ang II, the enzyme ACE2, and the AT 1 AT 2 and Mas receptors. Greater disease severity is also evident in male COVID-19 patients, which may reflect underlying sex differences in the regulation of the 2 distinct functional arms of the RAS. The current review provides a critical evaluation of the evidence for an activated RAS in COVID-19 subjects and whether this system contributes to the greater severity of severe acute respiratory syndrome-related coronavirus-2 infection in males as compared with females.