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. 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. Type 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. Myocardial 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. These 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.

中文翻译：

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内源性不对称二甲基精氨酸积累有助于抑制 2 型糖尿病大鼠的心肌线粒体生物发生。

据报道，线粒体生物合成受到抑制是导致糖尿病心肌病的线粒体功能障碍的早期信号，但线粒体生物合成抑制的机制尚不清楚。一氧化氮合酶抑制剂不对称二甲基精氨酸（ADMA）与糖尿病心血管并发症密切相关。本研究旨在确定内源性 ADMA 积累是否参与抑制糖尿病大鼠心肌线粒体的生物发生，并阐明大鼠心肌细胞中的潜在机制。采用高脂喂养加单次腹腔注射小剂量链脲佐菌素（35mg/kg）诱导2型糖尿病大鼠模型。测量线粒体基因与核基因的拷贝数比率以反映线粒体生物发生。通过双荧光素酶报告基因测定和免疫沉淀检测过氧化物酶体增殖物激活受体-γ辅激活因子-1α（PGC-1α）的启动子活性及其翻译后修饰。与对照大鼠相比，糖尿病大鼠心肌中的心肌 ADMA 含量增加并与心肌线粒体生物发生和心脏功能的抑制相关，同时与 PGC-1α 下调和解偶联蛋白 2 (UCP2) 上调相关。同样，ADMA 及其同源物可以抑制心肌线粒体生物发生和 PGC-1α 表达，增加 UCP2 表达和体外和体内氧化应激。此外，ADMA 还抑制启动子活性和 PGC-1α 表达，但促进其在大鼠心肌细胞中的蛋白质乙酰化和磷酸化。这些结果表明，内源性 ADMA 积累有助于抑制 2 型糖尿病大鼠的心肌线粒体生物发生。潜在的机制可能与降低 PGC-1α 启动子活性和表达但促进其蛋白质乙酰化和磷酸化有关。