The recent clinical case reports of COVID-19 published in The Lancet and The New England Journal of Medicine confirm that SARS-CoV-2 not only damages alveolar epithelial cells and causes respiratory failure, but also injures vascular endothelial cells of the lung and multiple organs and subsequently induces inflammatory storm and massive blood coagulation, eventually leading to multiple organ failure. Nevertheless, the molecular mechanism underlying SARS-CoV-2 entering and damaging vascular endothelial cells remains elusive.
To resolve this question, the team led by Professor Yuan Zuyi from Department of Cardiology of the First Affiliated Hospital of Xi 'an Jiaotong University (XJTU) and the team of Wang Shengpeng from Cardiovascular Research Center, School of Basic Medical Sciences of XJTU Health Science Center cooperated with the team led by Professor Uri Manor from Salk Institute for Biological Studies in the U.S. to discover, for the first time, that the SARS-CoV-2 spike protein (S protein) can cause vascular endothelial cell dysfunction via down-regulating ACE2. In this study, Syrian golden hamsters and ACE2-D and ACE2-L transgenic mice with phospho-ACE2S680 mutation were adopted.In vivoandin vitroexperiments showed that S protein decreased the activities of ACE2 and eNOS by down-regulating AMPK activity and decreasing ACE2 phosphorylation in endothelial cells, which was accompanied by abnormal morphology and declined mitochondrial function in endothelial cells, and reprogramming of glycolysis, eventually leading to the decreased pulmonary vasodilation function and pulmonary vascular injury. Down-regulation of ACE2 by S protein will reduce the virus infectivity, whereas ACE2 reduction tends to aggravate endothelial dysfunction and promote endothelial inflammation. These findings indicate that the antibody against S protein can not only protect the host from SARS-CoV-2 infectivity, but also inhibit S protein-imposed endothelial injury, and ultimately decrease the cardiovascular complication-associated mortality in COVID-19 patients. Therefore, the research teams proposed the double-edged sword theory of ACE2 in COVID-19 for the first time: ACE2 not only exerts the "negative effect" upon mediating SARS-CoV-2 invasion into the endothelium, but also imposes the "positive effect" on protecting vascular endothelial function.
These research results were published online entitled SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE2 in Circulation Research (IF=14.467) on March 31, 2021. The First Affiliated Hospital of XJTU is the first affiliation. Postgraduate Lei Yuyang and postdoctoral fellow Zhang Jiao from Department of Cardiology of our hospital are the co-first authors. Professor Yuan Zuyi from our hospital and Cardiovascular Research Center of XJTU, Professor Wang Shengpeng from School of Basic Medical Sciences, and Professor Uri Manor from Salk institute for Biological Studies are co-corresponding authors. This study was financially supported by Key and Surface Projects of National Natural Science Foundation of China and National Key Research and Development Plan,etc.
In addition, the research teams of our hospital and School of Basic Medical Sciences have obtained a series of research results regarding the protective mechanism of ACE2 in pulmonary vascular endothelium and the treatment process of patients with acute and critical cardiovascular diseases during COVID-19 pandemic. Relevant articles have been published in the international top-notch academic journals including Am J Respir Crit Care Med [IF=17.452, 2018 Aug 15; 198(4):509-520],Circulation [IF=23.603,Circulation 2020 Sep 22; 142(12):1190-1204] and Circulation [IF=23.603,Circulation 2020 May 19; 141(20):e810-e816], respectively.
Article link: https://www.ahajournals.org/doi/abs/10.1161/CIRCRESAHA.121.318902