Diabetes Promotes Myocardial Fibrosis via AMPK/EZH2/PPAR-γ Signaling Pathway

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Epigenetics

Background:

• Diabetes mellitus is a leading cause of heart disease, characterized by cardiac fibrosis and diabetic cardiomyopathy.
• Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, is implicated in fibrosis, but its role in diabetic heart disease is unclear.

Purpose of the Study:

• To elucidate the mechanism of EZH2 in diabetes-induced cardiac fibrosis.
• To identify key molecular pathways involved in high glucose-mediated cardiac fibroblast activation.

Main Methods:

• Establishment of rat and mouse diabetic models and in vitro high glucose (HG) stimulation of primary rat ventricular fibroblasts.
• Assessment of cardiac function (echocardiography) and fibrosis (Masson staining) in vivo.
• Analysis of histone H3 lysine 27 (H3K27) trimethylation, EZH2 expression/phosphorylation, and fibrotic markers in vitro and in vivo.

Main Results:

• Elevated H3K27 trimethylation and reduced EZH2 phosphorylation were observed in diabetic hearts and HG-treated fibroblasts.
• EZH2 inhibition (GSK126) attenuated HG-induced cardiac fibroblast activation, differentiation, migration, and fibrotic protein overexpression.
• High glucose inactivated AMP-activated protein kinase (AMPK), reducing EZH2 phosphorylation, which transcriptionally suppressed peroxisome proliferator-activated receptor γ (PPAR-γ) and promoted fibroblast activation.

Conclusions:

• An AMPK/EZH2/PPAR-γ signaling axis is identified as a critical mediator of high glucose-induced cardiac fibrosis.
• This pathway represents a potential therapeutic target for mitigating diabetic cardiomyopathy.