lncRNA-HypERlnc调控SIRT1蛋白SUMO化修饰参与心肌能量代谢调节及其在心肌肥厚中的作用及机制研究

Cardiac hypertrophy plays an important role in the occurrence and development of heart failure. The prevention of cardiac hypertrophy has important significance to reduce cardiac disease mortality rates. At present, the study has confirmed that lncRNA-HypERlnc expression is significantly reduced in human cardiac tissue from heart failure patients, nevertheless, the exact role and molecular mechanism of lncRNA-HypERlnc involved in cardiac energy metabolism and cardiac hypertrophy is unknown. The study has indicated that SIRT1 protein SUMO modification participated in the regulation of cardiac energy metabolism. The improvement of energy metabolism abnormality can treat the cardiac hypertrophy. Our studies showed that HypERlnc could antagonize cardiac hypertrophy; SP1 regulated the SUMO modification of SIRT1 protein and regulated cardiac energy metabolism. Therefore, we propose that HypERlnc may activate SP1, which is able to promote SUMOylation of SIRT1 protein, regulate cardiac energy metabolism for treatment of cardiac hypertrophy. To study the above hypothesis, we elucidate the effect and mechanism of HypERlnc in the regulation of cardiac energy metabolism for the treatment of cardiac hypertrophy in vitro and in vivo, which are evaluated using the technology of molecular biology, cytology and pathology. In conclusion, the study will have new insight into the prevention and treatment of cardiac hypertrophy, and development of innovative method for treatment of cardiac hypertrophy.

心肌肥厚是心力衰竭发生和发展的主要因素，研究其防治对降低心脏病致死率具有重要意义。目前发现lncRNA-HypERlnc在临床心衰患者心脏中显著减少，但其调控心肌能量代谢及心肌肥厚的作用及机制尚不清楚。研究证实SIRT1蛋白SUMO化修饰参与心肌能量代谢调节；改善能量代谢异常可以逆转心肌肥厚。我们在前期工作中发现：HypERlnc能够抑制心肌肥厚；SP1调控SIRT1蛋白SUMO化修饰，调节心肌能量代谢。因此，我们提出假设：HypERlnc可以通过调控心肌细胞中SP1的活性，促进SIRT1的SUMO化修饰，调节心肌能量代谢，治疗心肌肥厚。为了证实这一假设，我们将利用分子生物学、细胞学及病理学等技术方法，从分子、细胞、动物及临床水平探讨HypERlnc参与心肌能量代谢的作用，以及HypERlnc调控心肌肥厚的机制。通过本课题将为心肌肥厚的发病机理提供新的视野，并为防治心肌肥厚提供新的切入点。

心肌肥厚是一种以心室肌肥厚为主要特征的心肌病，在致病因素刺激下病程进展所发生的心力衰竭是最为常见的致死原因。近年来，对长链非编码RNA（long noncoding RNA, lncRNA）的深入研究为心肌肥厚的防治提供了新的方向。LncRNA-HypERlnc被发现在心力衰竭（HF）患者的心室心肌中表达显著减少。然而，HypERlnc对心肌肥厚的调控作用及机制尚不清楚。本课题采用心衰患者的血样标本和心肌细胞，利用qRT-PCR、Western Blot、免疫共沉淀及免疫荧光等技术方法，研究并发现HypERlnc在心衰患者血样和血管紧张素Ⅱ刺激的心肌细胞中表达均减少；HypERlnc过表达能够降低心肌细胞肥大并抑制肥大相关基因表达；并且HypERlnc能够通过上调PGC‐1α/PPARα信号通路改善血管紧张素Ⅱ诱导的心肌细胞能量代谢紊乱和线粒体损伤；同时，SIRT1的SUMO化修饰参与HypERlnc对心肌肥厚的抑制作用以及对能量代谢的改善。本课题对病理性心肌肥厚的发病机制进行了深入的研究并为其治疗提供了新的靶点。