Angiotensin-converting enzyme 2, feedback systems, and COVID-19

Salgo, M. P.

Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) are key components of the renin-angiotensin system (RAS), which maintains homeostasis of blood pressure, among other functions. ACE acts in a positive feedback loop, providing amplification, while ACE2, acting in a negative feedback loop, modulates the ACE action, providing stability and fine control. Certain demographic groups that are more likely to become infected with SARS-CoV-2, the virus that causes COVID-19-and once infected, to have more severe disease and higher mortality-have a deficiency of ACE2. ACE2 has recently been shown to be a major receptor by which SARS-CoV-2 enters cells. This entry process is associated with downregulation of ACE2. Thus, viral cell entry per se can interfere with the RAS feedback system. Viral penetration of cells using ACE2 can lead to a shift in the RAS from the usual “preventive” ACE2 axis to the “adverse” ACE axis of the feedback systems. This imbalance, with predominance of the adverse ACE axis, can lead to downstream actions of increased vasoconstriction, inflammation, and thrombosis. These, in turn, can affect end organs, initiating COVID-19-associated conditions such as cytokine storm, thrombosis, multisystem inflammatory syndrome in children, and acute respiratory distress syndrome. This focused review highlights the importance of feedback systems in our understanding of the disruption of ACE2 feedback and resulting clinical consequences in COVID-19.