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 COVID-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, anti-inflammation, 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.
【저자키워드】 Cardiology, Target identification, 【초록키워드】 COVID-19, Treatment, coronavirus disease, Transcriptome, Inflammation, Coronavirus disease 2019, Cytokines, Gene Expression, Genetic, Angiogenesis, cytokine, Anti-inflammation, antioxidant, Endothelial dysfunction, Cytokine release syndrome, monocyte, serum, endothelial cells, Patient, atorvastatin, molecular, disease, expression, RNA-sequencing, COVID-19 patients, Protective, TNF-α, Endothelial cell, IL-1β, Evidence, master regulator, cardiovascular complications, endothelial function, therapeutic target, leads, vascular disease, endothelial, tannic acid, effort, sequencing data, knockdown, overexpression, ICAM1, VCAM1, COVID-19 patient serum, KLF2, Pharmacologic, vascular homeostasis, vasodilation, approach, evaluate, elevated, reduced, treated, demonstrated, increase in, reversed, was reduced, precipitate, was increased, with COVID-19, 【제목키워드】 COVID-19, transcription factor, PROTECT,