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Meng-Dan Zhou 1 Article
Basic Research
Diabetes Promotes Myocardial Fibrosis via AMPK/EZH2/PPAR-γ Signaling Pathway
Shan-Shan Li, Lu Pan, Zhen-Ye Zhang, Meng-Dan Zhou, Xu-Fei Chen, Ling-Ling Qian, Min Dai, Juan Lu, Zhi-Ming Yu, Shipeng Dang, Ru-Xing Wang
Received February 3, 2023  Accepted November 13, 2023  Published online February 27, 2024  
DOI: https://doi.org/10.4093/dmj.2023.0031    [Epub ahead of print]
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AbstractAbstract PDFPubReader   ePub   
Background
Diabetes-induced cardiac fibrosis is one of the main mechanisms of diabetic cardiomyopathy. As a common histone methyltransferase, enhancer of zeste homolog 2 (EZH2) has been implicated in fibrosis progression in multiple organs. However, the mechanism of EZH2 in diabetic myocardial fibrosis has not been clarified.
Methods
In the current study, rat and mouse diabetic model were established, the left ventricular function of rat and mouse were evaluated by echocardiography and the fibrosis of rat ventricle was evaluated by Masson staining. Primary rat ventricular fibroblasts were cultured and stimulated with high glucose (HG) in vitro. The expression of histone H3 lysine 27 (H3K27) trimethylation, EZH2, and myocardial fibrosis proteins were assayed.
Results
In STZ-induced diabetic ventricular tissues and HG-induced primary ventricular fibroblasts in vitro, H3K27 trimethylation was increased and the phosphorylation of EZH2 was reduced. Inhibition of EZH2 with GSK126 suppressed the activation, differentiation, and migration of cardiac fibroblasts as well as the overexpression of the fibrotic proteins induced by HG. Mechanical study demonstrated that HG reduced phosphorylation of EZH2 on Thr311 by inactivating AMP-activated protein kinase (AMPK), which transcriptionally inhibited peroxisome proliferator-activated receptor γ (PPAR-γ) expression to promote the fibroblasts activation and differentiation.
Conclusion
Our data revealed an AMPK/EZH2/PPAR-γ signal pathway is involved in HG-induced cardiac fibrosis.

Diabetes Metab J : Diabetes & Metabolism Journal