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

Abstract

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.

Degradation of the α-Carboxyl Terminus 11 Peptide: In Vivo and Ex Vivo Impacts of Time, Temperature, Inhibitors, and Gender in Rat

“…24,45 While the biological activities of PTase/PPTases can be modulated by multiple factors, 25,55 as demonstrated in the present study (e.g., time and temperature), no statistically significant differences in αCT11 degradation were found between males and females under our current experimental conditions (Figure S1), suggesting that sex may not play a role in regulating αCT11 degradation. Interestingly, sex hormones (e.g., estrogen, progesterone, testosterone) are known to widely regulate numerous biological processes, not only directing the development of a sexual system but also affecting the renin− angiotensin system 69 and cardiac remodeling following MI. 70 Whether sex hormones directly or indirectly affect the activities of proteases and phosphatases, thus modulating peptide degradation, remains to be investigated.…”

Association of Renin-angiotensin pathway gene polymorphisms with COVID-19 susceptibility and severity in the Moroccan cohort

“…Understanding the underlying mechanisms driving disease severity is crucial for developing effective therapeutic interventions. Recent investigations have shed light on the potential involvement of the Renin-Angiotensin System (RAS), a vital hormonal regulatory system, in the pathogenesis and progression of COVID-19 (Chappell 2023). The RAS is a fundamental regulatory pathway responsible for maintaining homeostasis in the body, governing critical processes such as blood pressure control, electrolyte balance, and uid equilibrium.…”

COVID-19 and the Cardiovascular System: Requiem for a Medical Minotaur

“…9 COVID-19 severity in older males may also relate to lower testosterone, resulting in exaggerated mediation of inflammation, whereas estrogen modulation of the immune response may contribute to lower circulating proinflammatory cytokines, greater vascular protection, and reduced COVID-19 severity in women compared with men. 8 Vaccine-associated myocarditis and sex differences associated with it are also discussed in this compendium. The higher association of infection and vaccineassociated myocarditis in males aged 12 to 40, mirrors the general increased incidence of myocarditis in males younger than 50.…”

“…Sex differences in COVID-19 are further highlighted by Chappell, 8 relating differences in the renin-angiotensin system. Downregulation of ACE2, the receptor for SARS-CoV-2 binding and host cell internalization, may lead to a higher ratio of Ang II to Ang-(1-7) and des-Arg9 form of bradykinin due to reduced extracellular ACE2 activity.…”

“…Indeed, human platelets exhibit sex-differences in TLR7 expression as women have higher transcript level than men.9 COVID-19 severity in older males may also relate to lower testosterone, resulting in exaggerated mediation of inflammation, whereas estrogen modulation of the immune response may contribute to lower circulating proinflammatory cytokines, greater vascular protection, and reduced COVID-19 severity in women compared with men. 8 …”