Endogenous asymmetric dimethylarginine accumulation precipitates the cardiac and mitochondrial dysfunctions in type 1 diabetic rats.

Myocardial mitochondrial function and biogenesis are suppressed in diabetes, but the mechanisms are unclear. Increasing evidence suggests that asymmetric dimethylarginine (ADMA) is associated with diabetic cardiovascular complications. This study was to determine whether endogenous ADMA accumulation contributes to cardiac and mitochondrial dysfunctions of diabetic rats and elucidate the potential mechanisms. Diabetic rat was induced by single intraperitoneal injection of streptozotocin (50 mg/kg). N-acetylcysteine was given (250 mg/kg/d) by gavage for 12w. Cardiac function was detected by echocardiography. Left ventricle papillary muscles were isolated to examine myocardial contractility. Myocardial ATP and mitochondrial DNA contents were measured to evaluate mitochondrial function and biogenesis. Endogenous ADMA accumulation was augmented resulting in decreased nitric oxide (NO) production and increased oxidative stress, suggesting NO synthase (NOS) uncoupling in the myocardium of T1DM rats compared with control rats. ADMA augmentation was associated with cardiac and mitochondrial dysfunctions along with myocardial uncoupling protein-2 (UCP2) upregulation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) downregulation in T1DM rats. Exogenous ADMA could directly inhibit myocardial contractility, mitochondrial function and biogenesis in parallel with decreasing NO content and PGC-1α expression while increasing oxidative stress and UCP2 expression in papillary muscles and cardiomyocytes. Treatment with antioxidant N-acetylcysteine, also an inhibitor of NOS uncoupling, either ameliorated ADMA-associated cardiac and mitochondrial dysfunctions or reversed ADMA-induced NO reduction and oxidative stress enhance in vivo and in vitro. These results indicate that myocardial ADMA accumulation precipitates cardiac and mitochondrial dysfunctions in T1DM rats. The underlying mechanism may be related to NOS uncoupling, resulting in NO reduction and oxidative stress increment, ultimate PGC-1α down-regulation and UCP2 up-regulation.