Spike protein of SARS-CoV-2 downregulates ACE2 protein levels in ECs via the ubiquitin–proteasome system, which in turn leads to mitochondrial fragmentation, impaired endothelial nitric oxide (NO) synthase (eNOS) activity, dysregulated renin–angiotensin system, and severity of COVID-19 (9). This evidence concerns the gene REN and COVID-19.