Nicotinamide ribose prevents diabetic cardiomyopathy through promoting TET2-mediated active DNA demethylation in STZ-induced diabetic mice heart

Diabetic cardiomyopathy (DCM) has become an important complication of diabetes, and its pathogenesis is closely related to the disorder of active DNA methylation. Nicotinamide ribose (NR), as a derivative of vitamin B₃, has a hypoglycemic effect, but the effect of NR on preventing DCM is unknown. Then injection STZ (55 mg/kg/day) was used to establish a model of diabetic mice and 60% high-fat diet was fed for 12 weeks to establish DCM model mice. The diabetic mice were divided into three groups (n = 10), as follow: diabetic cardiomyopathies group (DCM, normal saline); metformin group (MET, 150 mg/kg/day metformin buffer); nicotinamide ribose group (NR, 400 mg/kg/day). Compared with the DCM group, the concentrations of fasting blood glucose and the fasting insulin were lower in NR group. NR intervention improved cardiac diastolic function, cardiomyocyte hypertrophy and fibrosis in diabetic mice. Additional, NR supplement up-regulated 5-hydroxymethylcystein (5hmC) levels, regulated TCA cycle and activated p-AMPK to enhance TET enzyme activity and TET2 protein stability in heart tissue of diabetic mice. And NR is beneficial for mitochondrial generation. In conclusion, this project systematical elucidated the molecular mechanism of NR improving DCM by regulating TET2 to promote active DNA demethylation, and provided a theoretical basis for NR's prevention and treatment of DCM.