Department of Pharmacology and Toxicology, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
Department of Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
Acta Physiol (Oxf). 2017 May;220(1):58-71. doi: 10.1111/apha.12800. Epub 2016 Oct 12.
The transcriptional cofactor receptor-interacting protein 140 (RIP140) is known as a deleterious regulator of cardiac mitochondrial function and energy metabolic homeostasis. This study revealed that RIP140 repressed Sirtuin 3 (SIRT3), a mitochondrial deacetylase that plays an important role in regulating cardiac function.
RIP140 was overexpressed by adenovirus infection or was knocked down by RNA interference in neonatal rat cardiomyocytes.
RIP140 overexpression repressed, while RIP140 silencing elevated the expression and activity of SIRT3. Ad-RIP140 enhanced the expressions of the cardiac hypertrophic markers and increased cardiomyocyte surface area, whereas SIRT3 overexpression prevented the effect of Ad-RIP140. Additionally, SIRT3 overexpression reversed Ad-RIP140-induced mitochondrial dysfunction and energy metabolic dysfunction, such as increase in oxidative stress, decrease in mitochondrial membrane potential and ATP production, as well as downregulation of mitochondrial DNA-encoded genes and genes related to mitochondrial genome replication and transcription, mitochondrial oxidative phosphorylation and fatty acid oxidation. In contrast, SIRT3 silencing exacerbated RIP140-induced cardiomyocyte hypertrophy and mitochondrial dysfunction. Furthermore, the repression of SIRT3 by RIP140 was dependent on estrogen-related receptor-α (ERRα). The involvement of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was ruled out of SIRT3 suppression by RIP140. RIP140 and PGC-1α might act as functional antagonists on the regulation of SIRT3.
This study indicates that suppression of SIRT3 by RIP140 facilitates the development of cardiomyocyte hypertrophy, mitochondrial dysfunction and energy metabolic dysfunction. Strategies targeting inhibition of RIP140 and upregulation of SIRT3 might improve cardiac energy metabolism and suggest therapeutic potential for heart diseases.
转录共激活因子受体相互作用蛋白 140（RIP140）被认为是心脏线粒体功能和能量代谢稳态的有害调节因子。本研究揭示了 RIP140 抑制了 Sirtuin 3（SIRT3），一种在线粒体去乙酰化中起重要作用的调节心脏功能的线粒体去乙酰化酶。
通过腺病毒感染过表达或 RNA 干扰敲低新生大鼠心肌细胞中的 RIP140。
RIP140 过表达抑制，而 RIP140 沉默则提高了 SIRT3 的表达和活性。Ad-RIP140 增强了心脏肥大标志物的表达并增加了心肌细胞表面积，而 SIRT3 过表达则阻止了 Ad-RIP140 的作用。此外，SIRT3 过表达逆转了 Ad-RIP140 诱导的线粒体功能障碍和能量代谢障碍，如氧化应激增加、线粒体膜电位和 ATP 产生减少，以及线粒体 DNA 编码基因和与线粒体基因组复制和转录、线粒体氧化磷酸化和脂肪酸氧化相关的基因下调。相反，SIRT3 沉默加剧了 RIP140 诱导的心肌细胞肥大和线粒体功能障碍。此外，RIP140 通过雌激素相关受体-α（ERRα）抑制 SIRT3。排除了 RIP140 对 SIRT3 的抑制作用依赖于过氧化物酶体增殖物激活受体-γ 共激活因子-1α（PGC-1α）。RIP140 和 PGC-1α 可能在 SIRT3 的调节中作为功能拮抗剂。
本研究表明，RIP140 抑制 SIRT3 促进了心肌细胞肥大、线粒体功能障碍和能量代谢障碍的发展。靶向抑制 RIP140 和上调 SIRT3 的策略可能改善心脏能量代谢，并为心脏病提供治疗潜力。
