Increased plasma ACE2 concentration does not mean increased risk of SARS-CoV-2 infection and increased fatality rate of COVID-19

摘要

A model for the process of SARS-CoV-2 entering host cells in the lungs and heart and the relationship among ACE2, the RAAS, the apelin-APJ system and SARS-CoV-2 in the pathogenesis of COVID-19. In addition to ACE2 receptor, ADAM17, TMPRSS2, CD147, GRP78, furin, cathepsin B and cathepsin L may mediate the viral binding and entry processes of SARS-CoV-2 infection. Membrane-bound ACE2 (mACE2) catalyzes Ang II conversion to protective peptide Ang-(1–7) and also serves as the major SARS-CoV-2 receptor, directly mediating the endocytosis of SARS-CoV-2 via binding to the Spike protein. ACE2-mediated cardiopulmonary protection is lost following endocytosis of the enzyme along with SARS-CoV-2 viral particles. Ang II level elevates with increased activity of AT1R and further increases ADAM17 activity at the cost of the ACE2/Ang-(1–7)–Mas axis and apelin–APJ axis driven pathways leading to adverse fibrosis, hypertrophy, increased ROS generation, vasoconstriction, and inflammation. The resultant cell-surface downregulation of ACE2 after SARS-CoV-2 infection contributes to the ongoing cardiopulmonary damage and a cytokine storm due to lower Ang-(1–7)/Ang II ratio (left). Importantly, recombinant human ACE2 (rhACE2) and soluble ACE2 (sACE2) may act as a virus trap and inactivator for SARS-CoV-2 along with higher Ang-(1–7)/Ang II ratio (right). Thus, rhACE2, sACE2, ACE2-Fc, ACE2-Ig, apelin and APJ agonists are currently considered as potentially therapeutic options for COVID-19 patients with SARS-CoV-2.