Endogenous asymmetric dimethylarginine accumulation contributes to the suppression of myocardial mitochondrial biogenesi
- PDF / 3,283,216 Bytes
- 17 Pages / 595.276 x 790.866 pts Page_size
- 1 Downloads / 177 Views
RESEARCH
Open Access
Endogenous asymmetric dimethylarginine accumulation contributes to the suppression of myocardial mitochondrial biogenesis in type 2 diabetic rats Yan Xiong1,2,3* , Chun-Xia Hai3, Wei-Jin Fang2, Yan-Ping Lei2, Xiao-Mei Li1,2 and Xin-Ke Zhou1*
Abstract Background: 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. Methods: 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 coactivator1α (PGC-1α) and its post-translational modifications were detected by dual-luciferase reporter assay and immunoprecipitation. Results: 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. Conclusions: 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. Keywords: Asymmetric dimethylarginine, Diabetic cardiomyopathy, Mitochondrial biogenesis, Peroxisome proliferator-activated receptor-γ coactivator-1α
* Correspondence: [email protected]; [email protected] This study was supported by grants from the Natural Science Research Foundation of Guangdong Province and China (2016A030311050 and 81570751 & 81170778) 1 Department of Central Laboratory, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, Guangdong, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate c
Data Loading...
