Abstract
ACE2 (angiotensin-converting enzyme 2), a multifunctional transmembrane protein, is well recognized as an important member of the (RAS) renin-angiotensin system with important roles in the regulation of cardiovascular function by opposing the harmful effects of Ang-II (angiotensin II) and AT1R (Ang-II type 1 receptor) activation. More recently, ACE2 was found to be the entry point for the SARS-CoV-2 virus into cells, causing COVID-19. This finding has led to an exponential rise in the number of publications focused on ACE2, albeit these studies often have opposite objectives to the preservation of ACE2 in cardiovascular regulation. However, notwithstanding accumulating data of the role of ACE2 in the generation of angiotensin-(1-7) and SARS-CoV-2 internalization, numerous other putative roles of this enzyme remain less investigated and not yet characterized. Currently, no drug modulating ACE2 function or expression is available in the clinic, and the development of new pharmacological tools should attempt targeting each step of the lifespan of the protein from synthesis to degradation. The present review expands on our presentation during the 2023 Lewis K. Dahl Memorial Lecture Sponsored by the American Heart Association Council on Hypertension. We provide a critical summary of the current knowledge of the mechanisms controlling ACE2 internalization and intracellular trafficking, the mutual regulation with GPCRs (G-protein-coupled receptors) and other proteins, and posttranslational modifications. A major focus is on ubiquitination which has become a critical step in the modulation of ACE2 cellular levels.