N-3 polyunsaturated fatty acids prevent diabetic cardiomyopathy by promoting TET2-mediated DNA demethylation

Diabetes cardiomyopathy (DCM) has become an important complication of diabetes, and its pathogenesis is closely related to the disorder of active DNA methylation. It has been reported that n-3 polyunsaturated fatty acids (PUFAs) improved insulin resistance and cardiovascular function, however the underlay molecular mechanism is unknown. The mice were fed with high-fat diet and injected with STZ (55mg/kg/d) for 7 consecutive days. Diabetes mice were fed with high-fat diet for another 12 weeks to induce diabetes cardiomyopathy (DCM), DCM mice were then divided into four groups (n=15): DCM group (normal saline); metformin group (MET, 150 mg/kg/d metformin buffer); low-dose n-3 PUFAs group (Ln-3, 150 mg/kg/d); high-dose n-3 PUFAs group (Hn-3, 300 mg/kg/d). The control (CON) group was fed with a standard diet (normal saline). Fasting serum concentrations of insulin, total cholesterol (TC), triglycerides (TG), low-density lipoprotein levels (LDL-C), and the atherogenic index of plasma (AIP) were significantly lower in both Ln-3 and Hn-3 groups than in DCM group. Total n-3 PUFAs and n-3/n-6 ratio in heart were significantly lower in DCM group than in CON, Ln-3 and Hn-3 groups. The ejection fraction (EF), fractional shortening (FS), early diastolic mitral annular velocity (E’/A’) were significantly lower in DCM group than in CON and Hn-3 groups. The left ventricular mass index (LV mass index) and left ventricular posterior wall thickness in systole (LVPW; s) were significantly lower in CON, Ln-3 and Hn-3 groups than in DCM group. The protein expression levels of TET2 and p-AMPKα/ AMPKα in mice heart of the Hn-3 group were significantly higher than those in the DCM group. The ratio of α-ketoglutarate to (succinate + fumarate) in the DCM group was significantly lower than that in the Ln-3 and Hn-3 groups. In conclusion, n-3 PUFAs prevented the occurrence of DCM by promoting TET2-mediated DNA demethylation in diabetic mice heart.