Cross talk between SARS-CoV-2 and the angiotensin system: clinical implications

Angiotensin-converting enzyme 2 (ACE2), serving as a receptor to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a key player in renin-angiotensin-aldosterone system (RAAS). Consequent ACE2 depletion disrupts the balance between the angiotensin II (Ang-II)/angiotensin 1 receptor (AT1R) and angiotensin 1-7 (Ang 1-7)/Mas receptor (MasR) arms of the angiotensin system, promoting intense inflammation. A cross talk existing between the angiotensin system and ACE2/spike proteins that may affect infection severity, with potential therapeutic implications. Evaluating such potential interactions and their relevance to the severity of coronavirus disease 2019 (COVID-19), which is directly affected by ACE2 abundance or indirectly by RAAS axis dysregulation. The intensity of SARS-CoV-2 infection was assessed using a cell-to-cell fusion assay, and AT1R activation was assessed using AT1R-Tango approach. We demonstrate the critical function of ACE2 in mitigating AT1R activation, which is disrupted following SARS-CoV-2 infection. Moreover, we show that the spike protein indirectly intensifies AT1R activation. Beyond its established role in activating MasR, Ang 1-7 was found to function as a biased agonist for AT1R, without altering ACE2 levels or affecting SARS-CoV-2 entry. In contrast, AVE0991, a MasR agonist, was observed to increase ACE2 levels and enhance SARS-CoV-2 infection. Angiotensin receptor blockers (ARBs) effectively inhibited AT1R activity and had minimal impact on viral entry. Our data support the likelihood that AT1R blockers (ARBs) may be effective in managing COVID-19 since they inhibit AT1R activation and its deleterious subsequent effects, with no impact on SARS-CoV-2 entry. By contrast, MasR and its agonist AVE0991, by increasing ACE2 levels, may restore RAAS physiological balance, but facilitate host cell invasion by SARS-CoV-2.NEW & NOTEWORTHY This study characterizes the interaction between the angiotensin system and angiotensin-converting enzyme 2 (ACE2)/spike proteins and its significance for coronavirus disease 2019 (COVID-19) severity. Using a cell-to-cell fusion assay and angiotensin 1 receptor (AT1R) activation assessment via the AT1R-Tango approach, we reveal a crucial role of ACE2 in attenuating AT1R activation. Furthermore, the data indicate that the spike protein indirectly amplifies AT1R activation. In addition, angiotensin 1-7 (Ang 1-7) was identified to act not only as Mas receptor (MasR) agonist, but also as a biased agonist for AT1R.