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Endothelial KLF11 is a novel protector against diabetic atherosclerosis.

Authors :
Zhao, Guizhen
Zhao, Yang
Liang, Wenying
Lu, Haocheng
Liu, Hongyu
Deng, Yongjie
Zhu, Tianqing
Guo, Yanhong
Chang, Lin
Garcia-Barrio, Minerva T.
Chen, Y. Eugene
Zhang, Jifeng
Source :
Cardiovascular Diabetology. 10/26/2024, Vol. 23 Issue 1, p1-21. 21p.
Publication Year :
2024

Abstract

Background: Atherosclerotic cardiovascular diseases remain the leading cause of mortality in diabetic patients, with endothelial cell (EC) dysfunction serving as the initiating step of atherosclerosis, which is exacerbated in diabetes. Krüppel-like factor 11 (KLF11), known for its missense mutations leading to the development of diabetes in humans, has also been identified as a novel protector of vascular homeostasis. However, its role in diabetic atherosclerosis remains unexplored. Methods: Diabetic atherosclerosis was induced in both EC-specific KLF11 transgenic and knockout mice in the Ldlr−/− background by feeding a diabetogenic diet with cholesterol (DDC). Single-cell RNA sequencing (scRNA-seq) was utilized to profile EC dysfunction in diabetic atherosclerosis. Additionally, gain- and loss-of-function experiments were conducted to investigate the role of KLF11 in hyperglycemia-induced endothelial cell dysfunction. Results: We found that endothelial KLF11 deficiency significantly accelerates atherogenesis under diabetic conditions, whereas KLF11 overexpression remarkably inhibits it. scRNA-seq profiling demonstrates that loss of KLF11 increases endothelial-to-mesenchymal transition (EndMT) during atherogenesis under diabetic conditions. Utilizing gain- and loss-of-function approaches, our in vitro study reveals that KLF11 significantly inhibits EC inflammatory activation and TXNIP-induced EC oxidative stress, as well as Notch1/Snail-mediated EndMT under high glucose exposure. Conclusion: Our study demonstrates that endothelial KLF11 is an endogenous protective factor against diabetic atherosclerosis. These findings indicate that manipulating KLF11 could be a promising approach for developing novel therapies for diabetes-related cardiovascular complications. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
14752840
Volume :
23
Issue :
1
Database :
Academic Search Index
Journal :
Cardiovascular Diabetology
Publication Type :
Academic Journal
Accession number :
180500562
Full Text :
https://doi.org/10.1186/s12933-024-02473-y