The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction

Abstract

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.

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19

“…The effects of COVID-19 patient plasma on endothelial cells are notable in 2 related but distinct ways. First, there is a coordinated response such that proinflammatory and prothrombotic genes are upregulated whereas anti-inflammatory or anti-thrombotic genes are downregulated ( 12 , 34 ). Second, the effects of the COVID humoral milieu extend to alterations of the endothelial cell surface that catalyze clot formation.…”

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication

“…High serum TNF-α and IL-1β levels in patients with COVID-19 may downregulate the Kruppel-like factor 2 (KLF2) expression in human endothelial cells, and subsequently induce monocyte adhesion, leading to endodermatitis characterized by endothelial dysfunction and hypercoagulability, and lymphocytic monocyte infiltration in patients with COVID-19. 122 IL-6 trans-signaling mediates the plasminogen activator inhibitor-1 (PAI-1) releasing from vascular endothelial cells in CRS. Increased levels of PAI-1 can result in endothelial dysfunction, induce cell senescence, thereby promoting local hypoxia.…”

Ferulic acid and berberine, via Sirt1 and AMPK, may act as cell cleansing promoters of healthy longevity

“…In this regard, it is topical to note that exposure of endothelial cells to serum from patients with COVID-19 or to SARS-CoV-2 spike protein diminishes KLF2 expression, possibly via enhanced proteasomal degradation 77 78. Moreover, enhancing KLF2 expression via transfection, bortezomib, or statins was found to suppress the proinflammatory, prothrombotic effects of COVID-19 serum or of spike protein on endothelial cells 77 78. Hence, ferulic acid/berberine may have potential for controlling the endotheliopathy associated with COVID-19 or SARS-CoV-2 spike protein exposure (as via mRNA vaccines) by upregulation of KLF2.…”