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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 \u03b3 (PPAR-\u03b3) expression to promote the fibroblasts activation and differentiation.Conclusion: Our data revealed an AMPK\/EZH2\/PPAR-\u03b3 signal pathway is involved in HG-induced cardiac fibrosis.<\/jats:p>","DOI":"10.4093\/dmj.2023.0031","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T23:24:05Z","timestamp":1708989845000},"page":"716-729","update-policy":"https:\/\/doi.org\/10.4093\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Diabetes Promotes Myocardial Fibrosis via AMPK\/EZH2\/PPAR-\u03b3 Signaling 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