SIRT۵ prevents mitochondrial dysfunction and cardiac hypertrophy induced by RIP۱۴۰

Objective(s): To investigate the effect and mechanism of Sirtuin۵ (SIRT۵) on mitochondrial dysfunction and cardiac hypertrophy induced by receptor-interacting protein ۱۴۰ (RIP۱۴۰).Materials and Methods: The neonatal rat cardiomyocytes (NRCMs) and SD rats were treated with Angiotensin II (Ang II) to induce in vitro and in vivo model of cardiac hypertrophy. RIP۱۴۰ was overexpressed by adenovirus infection, and SIRT۵ was overexpressed by plasmid transfection. RIP۱۴۰ and SIRT۵ were knocked down by siRNA interference. The expression of RIP۱۴۰, SIRT۵, and biomarkers of cardiac hypertrophy were measured by qRT-PCR and western blot. The transcription levels of mitochondrial DNA-encoded genes were detected by qRT-PCR. Cell surface area and mitochondrial membrane potential were respectively detected by rhodamine-phalloidin and tetramethylrhodamine ethyl ester (TMRE) fluorescence analysis. Cellular oxygen consumption and ATP production were investigated using assay kits. All data are from at least three independent experiments.Results: The expression of SIRT۵ was down-regulated in NRCMs and hearts treated with Ang II. Overexpression of SIRT۵ protected cardiomyocytes from AngII-induced hypertrophy, whereas knockdown of SIRT۵ resulted in cardiac hypertrophy. Moreover, since SIRT۵ was regulated by the transcriptional coactivator, we also found that SIRT۵ could be negatively regulated by the transcriptional corepressor RIP۱۴۰ in cardiomyocytes. Furthermore, SIRT۵ significantly attenuated energy metabolic dysregulation and mitochondrial dysfunction and exerted its protective role on myocardial hypertrophy under the regulation of RIP۱۴۰.Conclusion: SIRT۵ exerts a protective role in mitochondrial dysfunction and cardiac hypertrophy induced by RIP۱۴۰.

کلیدواژه ها:

Cardiac hypertrophy ، Energy metabolism ، Mitochondria ، RIP۱۴۰ ، SIRT۵