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

Suowen Xu; Yujie Liu; Yu Ding; Sihui Luo; Xueying Zheng; Xiumei Wu; Zhenghong Liu; Iqra Ilyas; Suyu Chen; Shuxin Han; Peter J Little; Mukesh K Jain; Jianping Weng

doi:10.1038/s41392-021-00690-5

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

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

Suowen Xu, Yujie Liu, Yu Ding, Sihui Luo, Xueying Zheng, Xiumei Wu, Zhenghong Liu, Iqra Ilyas, Suyu Chen, Shuxin Han, …

Signal Transduction and Targeted Therapy, Vol.6(1), pp.1-9

2021

DOI: https://doi.org/10.1038/s41392-021-00690-5

PMCID: PMC8273371

PMID: 34253708

Appears in COVID-19 Research

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Abstract

Kruppel-like factor-2

expression

injury

COVID-19

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.

Details

Title: The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction
Authors: Suowen Xu (Author) - University of Science and Technology of China
Yujie Liu (Author) - University of Science and Technology of China
Yu Ding (Author) - University of Science and Technology of China
Sihui Luo (Author) - University of Science and Technology of China
Xueying Zheng (Author) - University of Science and Technology of China
Xiumei Wu (Author) - Sun Yat-sen University
Zhenghong Liu (Author) - University of Science and Technology of China
Iqra Ilyas (Author) - University of Science and Technology of China
Suyu Chen (Author) - University of Science and Technology of China
Shuxin Han (Author) - University of Science and Technology of China
Peter J Little (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - Legacy
Mukesh K Jain (Author) - Case Western Reserve University
Jianping Weng (Author) - University of Science and Technology of China
Publication details: Signal Transduction and Targeted Therapy, Vol.6(1), pp.1-9
Publisher: Nature Publishing Group
Date published: 2021
DOI: 10.1038/s41392-021-00690-5
ISSN: 2059-3635
PMID: 34253708; PMC8273371
Copyright note: Copyright (C) 2021 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Organisation Unit: School of Health; University of the Sunshine Coast, Queensland; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99572408902621
Output Type: Journal article

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