摘要
Coronavirus disease 2019(COVID-19)is regarded as an endothelial disease(endothelialitis)with its patho-mechanism being incompletely understood.Emerging evidence has demonstrated that endothelial dysfunction precipitates COVID-19 and its accompanying multi-organ injuries.Thus,pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications.The objective of the present study is to evaluate whether kruppel-like factor 2(KLF2),a master regulator of vascular homeostasis,represents a therapeutic target for C0VID-19-induced endothelial dysfunction.Here,we demonstrate that the expression of KLF2 was reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules,ICAM1 and VCAM1.IL-1β and TNF-α;two cytokines elevated in cytokine release syndrome in COVID-19 patients,decreased KLF2 gene expression.Pharmacologic(atorvastatin and tannic acid)and genetic(adenoviral overexpression)approaches to augment KLF2 levels attenuated COVID-19-serum-induced increase in endothelial inflammation and monocyte adhesion.Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function(vasodilation,antiinflammation,antioxidant status,anti-thrombosis/-coagulation,anti-fibrosis,and reduced angiogenesis).Finally,knockdown of KLF2 partially reversed the ameliorative effect of atorvastatin on COVID-19-serum-induced endothelial inflammation and monocyte adhesion.Collectively,the present study implicates loss of KLF2 as an important molecular event in the development of COVID-19-induced vascular disease and suggests that efforts to augment KLF2 levels may be therapeutically beneficial.
基金
This study is funded by the Fundamental Research Funds for the Central Universities(Grant Nos.YD9110004001 and,YD9110002002,and YD9110002008)
Hefei Municipal Development and Reform Commission Emergency Funding for COVID-19 disease(Grant No.BJ9100000005)
This study was also supported by grants from National Natural Science Foundation of China(Grant Nos.81941022,82070464)
Strategic Priority Research Program of Chinese Academy of Sciences(Grant No.XDB38010100)
This work was also supported by Program for Innovative Research Team of The First Affiliated Hospital of USTC(CXGG02)
Anhui Provincial Key Research and Development Program(Grant No.202104j07020051)
Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(Grant No.2017BT01S131).
