Resveratrol improves diabetic cardiomyopathy by preventing asymmetric dimethylarginine-caused peroxisome proliferator-activated receptor-? coactivator-1? acetylation

Objectives: Cardiac protection of resveratrol is related to the improvement of mitochondrial function through sirtuin1 (SIRT1) activation and peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) deacetylation. Asymmetric dimethylarginine (ADMA) as an endogenous inhibitor of nitric oxide synthases is associated with diabetic cardiovascular complications and has a cross-talk with lysine acetylation. This study was to determine whether resveratrol reverses ADMA's pathogenic role in diabetic cardiomyopathy and elucidate the underlying mechanisms in type 2 diabetic (T2DM) rats and cardiomyocytes.Methods: T2DM Rats were induced by high-fat diet plus small-dose streptozotocin injection (35 mg/kg). Resveratrol was given by gavage (50 mg/kg/d) to some rats for 16w. Cardiac function was measured by echocardiography, and PGC-1 alpha acetylation was detected by immunoprecipitation. Mitochondrial DNA and ATP contents were analyzed to evaluate mitochondrial biogenesis and function.Results: Endogenous ADMA accumulation and its signal disorders were associated with cardiac and mitochondrial dysfunctions in accompany with increased PGC-1 alpha acetylation and decreased PGC-1 alpha expression in the myocardium of T2DM rats compared with control rats. Resveratrol treatment attenuated ADMA accumulation, cardiac and mitochondrial dysfunctions in parallel with reversing altered PGC-1 alpha expression and acetylation in the myocardium of T2DM rats. Exogenous ADMA not only reproduced mitochondrial dysfunction and cardiac hypertrophy but also reduced PGC-1 alpha expression and enhanced PGC-1 alpha acetylation in accompany of downregulating SIRT1 and up-regulating acetyltransferase expression, all of which could be prevented by resveratrol pretreatment in cardiomyocytes.Conclusions: These results indicate that ADMA promotes PGC-1 alpha acetylation as a potential therapeutic target for resveratrol of management diabetic cardiomyopathy in T2DM rats.

Automated summary

The study found that resveratrol improves mitochondrial function and protects the heart by activating SIRT1 and deacetylating PGC-1 alpha. Additionally, resveratrol can reverse the pathogenic role of ADMA in diabetic cardiomyopathy and restore altered PGC-1 alpha expression and acetylation. Exogenous ADMA reproduces cardiac and mitochondrial dysfunction, which can be prevented by resveratrol pretreatment.