Coronavirus Disease 2019 (COVID-19) infects host cells through the binding of the spike (S) glycoprotein of the SARS-CoV-2 to ACE2 (angiotensin-converting enzyme 2). Infection of vascular endothelium with SARS-CoV-2 elicits a glycolytic shift and results in reactive oxygen species production in the mitochondria. ACE2 is localized in the lungs, gastrointestinal tract, nasal mucosa, heart, kidneys, and liver. Therefore, multiple organ vasculitis and inflammation can be produced by SARS-CoV-2. More importantly, factors such as age, co-morbidities (hypertension, diabetes, blood clotting disorders, obesity) among others, are risk factors in COVID-19 patients that lead to cardiovascular complications in addition to respiratory disease.
In this paper, the authors showed that the SARS-CoV-2 spike protein decreased levels of ACE2 in lungs, impaired mitochondrial function, and ultimately destabilized ACE2.
Syrian hamsters challenged with a non-infectious pseudovirus-expressing S protein showed thickening of the alveolar septa and increased infiltration of mononuclear cells.
Confocal images of human arterial endothelial cells (ECs) treated with the S protein revealed mitochondrial fragmentation, suggesting an alteration in mitochondrial dynamics.
In vitro oxygen consumption and extracellular acidification rate assays found that dephospho-mimetic ACE2 reduced basal mitochondrial respiration and ATP production in ECs.
In vivo acetylcholine- and sodium nitroprusside-induced vasodilation experiments showed that vasodilation is hindered in pulmonary arteries by dephospho-mimetic ACE2.
Western blots showed downregulation of the pACE2Ser480/ACE2 expression in infected hamster lung tissue and in human arterial ECs.
Authors hypothesised that ACE2 reduction might decrease SARS-CoV-2 virus infectivity, thereby protecting endothelium. However, ACE2 reduction led to dysfunctional endothelium because ACE2 is protective in the cardiovascular system. The work from Lei Y and colleagues published this year in Circulation Research illuminates key steps in the mechanism by which SARS-CoV-2 leads to vascular damage. These findings suggested that vaccination not only protects from infection but also inhibits endothelial damage in patients with COVID-19.
Lei Y, Zhang J, Schiavon CR, He M, Chen L, Shen H, Zhang Y, Yin Q, Cho Y, Andrade L, Shadel GS, Hepokoski M, Lei T, Wang H, Zhang J, Yuan JX, Malhotra A, Manor U, Wang S, Yuan ZY, Shyy JY. SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE2. Circ. Res. 2021 Apr 30;128(9):1323-1326