In culture of pneumocytes, the ACEI/ARB-induced mACE2 up-regulation was associated with ADAM17 inhibition and reduced SARS-CoV-2 spike protein entry
(A) In in vitro experiment, binding the SARS-CoV-2 spike protein on mACE2 resulted in spike protein internalization associated with the reduction in mACE2 levels, whereas the levels of short ACE2 in pneumocytes (intACE2) and sACE2 in culture medium increased. Furthermore, spike protein induced an increase in ADAM17 enzymatic activity and pro-inflammatory cytokine levels (TNF-α, IL-6 and CCL2) in culture medium. (B) ACEI/ARB prevented spike protein internalization and the decline of mACE2 levels, suggesting reduced mACE2 shedding. Importantly, ACEI/ARB hampered the spike protein-induced increase in ADAM17 activity. Moreover, ACEI/ARB alleviated the spike protein-induced pro-inflammatory cytokine response [15]. Abbreviation: intACE2, internalized cellular ACE2. Created with BioRender.com.