Abstract
BackgroundSuppressed mitochondrial biosynthesis has been reported to be the early signal of mitochondrial dysfunction which contributes to diabetic cardiomyopathy, but the mechanism of mitochondrial biosynthesis suppression is unclear. Nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is closely related to diabetic cardiovascular complications. This study was to determine whether endogenous ADMA accumulation was involved in the suppression of myocardial mitochondrial biogenesis in diabetic rats and to elucidate the potential mechanism in rat cardiomyocytes.MethodsType 2 diabetic rat model was induced by high-fat feeding plus single intraperitoneal injection of small dose streptozotocin (35 mg/kg). The copy number ratio of mitochondrial gene to nuclear gene was measured to reflect mitochondrial biogenesis. The promoter activity of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and its post-translational modifications were detected by dual-luciferase reporter assay and immunoprecipitation.ResultsMyocardial ADMA content was enhanced and associated with suppressions of myocardial mitochondrial biogenesis and cardiac function in parallel with PGC-1α downregulation and uncoupling protein 2 (UCP2) upregulation in the myocardium of diabetic rats compared with control rats. Similarly, ADMA and its homolog could inhibit myocardial mitochondrial biogenesis and PGC-1α expression, increase UCP2 expression and oxidative stress in vitro and in vivo. Moreover, ADMA also suppressed the promoter activity and PGC-1α expression but boosting its protein acetylation and phosphorylation in rat cardiomyocytes.ConclusionsThese results indicate that endogenous ADMA accumulation contributes to suppression of myocardial mitochondrial biogenesis in type 2 diabetic rats. The underlying mechanisms may be associated with reducing PGC-1α promoter activity and expression but boosting its protein acetylation and phosphorylation.
Highlights
Suppressed mitochondrial biosynthesis has been reported to be the early signal of mitochondrial dysfunction which contributes to diabetic cardiomyopathy, but the mechanism of mitochondrial biosynthesis suppression is unclear
Impairment of cardiac function in type 2 diabetes mellitus (T2DM) rats As presented in Table 4, the ejection fraction (EF) and fraction shortening (FS) of left ventricle were notably reduced in T2DM rats compared with control rats (P < 0.01); the isovolumic relaxation time (IVRT) of left ventricle was significantly prolonged, while the E/A ratio of early (E) to late (A) left ventricular filling velocities was greatly decreased in diabetic rats compared with control rats (P < 0.01), indicating the impairments of left ventricular diastolic and systolic functions in diabetic rats
asymmetric dimethylarginine (ADMA) significantly reduced silent information regulator homolog 1 (Sirt1) expression in cardiomyocytes (Fig. 7g & h, P < 0.01). These results indicated that ADMA could down-regulate Sirt1 expression and upregulate Pprotein kinase B (Akt) activation resulting in enhances of PGC-1α acetylation and phosphorylation in cardiomyocytes
Summary
Suppressed mitochondrial biosynthesis has been reported to be the early signal of mitochondrial dysfunction which contributes to diabetic cardiomyopathy, but the mechanism of mitochondrial biosynthesis suppression is unclear. The most prominent function of mitochondria is to produce energy in the form of ATP through oxidation-phosphorylation, which can be destroyed by the uncoupling protein 2 (UCP2). As a proton channel protein located in mitochondrial inner membrane, UCP2 can mediate protons leak leading to the uncoupling of oxidation phosphorylation and the reduction of mitochondrial ATP (mtATP) production [4, 5]. Even the suppressed mitochondrial biogenesis and impaired mitochondrial activity have been reported to occur in skeletal muscle of young, lean, normoglycemic, insulin-resistant offspring of parents with type 2 diabetes mellitus (T2DM) [14, 15]. Decreased mitochondrial biogenesis has been recognized as an initial factor of mitochondrial dysfunction in diabetes and a hallmark of high cardiovascular risk in metabolic diseases [16, 17]
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