线粒体能量代谢紊乱与心衰发生发展密切相关，以改善存活心肌代谢为目标的治疗方案已彰显成效，但迄今仍未有药物被证实能直接靶向代谢酶或蛋白纠正心衰代谢紊乱。RIP140是调控脂肪细胞、骨骼肌脂肪酸氧化和氧化磷酸化的转录辅抑制因子。但其对心肌（尤其在心衰中）能量代谢调控的机制仍不清楚。我们前期结果发现过表达RIP140抑制心肌能量代谢、诱导线粒体功能紊乱并加速心衰发病进程。心脏线粒体功能紊乱是导致线粒体产能障碍的重要因素，NF-κB介导的炎症反应是诱发心衰线粒体功能紊乱的关键。新生鼠心肌细胞中，我们发现过表达RIP140促进TNF-α等炎症因子分泌，诱导P65核转位，增强与NF-κB的结合活性。本课题将在此基础上进一步探讨RIP140能否直接结合并辅激活P65以及P65激活后影响线粒体产能和心脏功能的机制。为确立抑制RIP140介导的NF-κB/P65炎症通路作为心衰代谢治疗新靶点提供重要依据。

Collective evidences show that mitochondrial energy metabolic derangements are associated with the development and progress of heart failure. Targeting myocardial enegetics in the viable and potentially salvageable tissue may be particularly effective, but there is currently no approved drugs that directly target metabolic enzymes or proteins in heart failure. The transcriptional corepressor RIP140 is a master regulator of oxidation phosphorylation and fatty acid oxidation genes expression in adipocytes and skeletel muscle, but the exact mechanism of RIP140 in regulating cardiac energy metabolism, espcially during the progression of heart failure, is still unknown. Previously, our preliminary experiment found that overexpressing RIP140 repressed cardiac energy metabolism，induced mitochondrial dysfunction and accelerated the progress of heart failure. Mitochonrial dysfunction in advanced heart failure has been linked to impaired myocardial energetics. NF-κB-mediated inflammation pathways are critical for mitochonrial dysfunction in heart failure. In cultured neonatal rat cardiomyocytes, we observed that RIP140 upregulated proinflammatory gene expression and cytokines release(TNF-α, IL-2), induced the translocation of P65 protein from cytoplasm to nucleus, and enhanced the NF-κB binding activity. Intrigued by these findings, we further aim to explore whether RIP140 can interact and coactivate p65 directly and elucidate the mechanism of P65 activation for the capacity of ATP production in mitochondrial and cardial dyfunction in heart failure? Our research will provide an important basis for a new theraputic target against heart failure by repressing the RIP140-mediated NF-κB/P65 inflammation pathway.

NF-κB的激活不仅具有广泛的促炎症效应，还调控着心肌肥大、心力衰竭等心血管疾病的能量代谢。RIP140是核受体和转录因子重要的辅助抑制因子，抑制心脏线粒体能量代谢。为明确RIP140调控的线粒体能量代谢是否与NF-κB炎症通路密切相关，我们通过腺病毒载体使乳鼠心肌细胞及大鼠心肌过表达RIP140并观察到RIP140能够上调TNF-α、IL-2等炎症因子的基因表达与分泌，促进P65蛋白的核转位、增强NF-κB的核酸结合活性。RIP140诱导NF-κB/P65激活的同时，抑制代谢调节子PPARa及下游靶点的表达，导致线粒体功能紊乱。敲除P65能明显减弱RIP140对线粒体代谢的抑制作用，说明NF-κB的P65亚型参与RIP140介导的心脏炎症激活与代谢抑制。此外，借助心肌梗死的心脏疾病模型，通过向心肌多点注射过表达RIP140基因的腺病毒载体，我们发现过表达RIP140与心肌梗死4周后心脏、线粒体结构与功能受损程度相当。在心肌梗死应激下再过表达RIP140，加剧了心脏功能的恶化，梗死心肌向心衰疾病进展。上述研究为确立RIP140介导的NF-κB/P65炎症通路作为心衰代谢治疗新靶点提供重要依据。