Dapagliflozin Reduces Myocardial Injuries Through Modulation of H3K27me3 and SIRT1 in the Male Rat Model of Myocardial Ischemia Reperfusion.

Abstract

Abstract: Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, exhibits cardioprotective effects; however, the underlying epigenetic and molecular mechanisms remain poorly understood. This study investigated whether DAPA mitigates myocardial ischemia/reperfusion injury (MI/RI) by modulating enhancer of zeste homolog 2 (EZH2), trimethylation of lysine 27 on histone H3 (H3K27me3), and sirtuin 1 (SIRT1) expression. Wistar rats were randomly assigned to Sham, MI, and MI+DAPA groups (n = 12/group). MI groups underwent 30 minutes of left anterior descending coronary artery (LAD) ligation. For 14 days, animals in the MI+DAPA group received orally 1 mg/kg/day DAPA. Heart function, fibrosis, inflammatory factors (TNF-α, NF-κB, IL-1β, IL-6), and oxidative stress were assessed using echocardiography, Masson trichrome staining, Western blotting, and ELISA, respectively. EZH2, H3K27me3, and SIRT1 expression levels were also determined by Western blotting 14 days after MI induction. Tissue damage was evaluated using hematoxylin and eosin (H&E) staining. DAPA administration significantly improved MI-induced myocardial damage by decreasing serum levels of LDH, cTnI, and CK-MB. DAPA also improved left ventricular function by increasing ejection fraction (EF) and fractional shortening (FS), decreased left ventricular fibrosis, and reduced myocardial inflammation by improving myocardial TNF-α, NF-κB, IL-1β, and IL-6. In addition, DAPA reduced oxidative stress by decreasing malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD) activity. Finally, DAPA downregulated EZH2, reducing H3K27me3 and subsequently increasing SIRT1 levels compared with the MI group. This study's results indicate that DAPA attenuates MI/RI in male rats by modulating epigenetic mechanisms, specifically through EZH2, and H3K27me3 suppression and SIRT1 upregulation, offering novel insights into its cardioprotective potential.