HINT2在心肌肥厚中的作用及机制研究

能量重构和线粒体自噬是调节心肌肥厚的重要机制。HINT2是调节能量重构和线粒体自噬的关键分子，尚无对心肌肥厚的研究报道。我们前期研究结果显示HINT2可能发挥抑制心肌肥厚作用。因此我们推测HINT2可通过改善线粒体氧化呼吸链的功能、调节线粒体自噬及AMPK/PINK1信号通路改善心肌肥厚。本项目拟应用HINT2基因敲除与心脏特异性转基因小鼠，建立压力负荷诱导的心肌肥厚模型，从心脏功能、大体观察、组织病理、分子标志物表达等多个层面研究HINT2对心肌肥厚、纤维化和凋亡的影响；进一步探讨HINT2对心肌能量代谢、线粒体自噬、AMPK及其他信号转导通路的影响，初步明确HINT2影响心肌肥厚的机制；体外培养NRCM，沉默或过表达HINT2，观察HINT2对AngII 诱导的心肌细胞肥大、凋亡、线粒体自噬及信号通路的影响。阐明HINT2在心肌肥厚中的作用与机制，探寻防治心肌肥厚与心衰的新策略。

Energy remodeling and mitochondrial autophagy are important mechanisms for regulating cardiac hypertrophy.HINT2 is a key molecule that regulates energy remodeling and mitochondrial autophagy,and there is no report in cardiac hypertrophy.Our preliminary findings showed that HINT2 may play a protective role in cardial hypertrophy.Therefore,we speculate that HINT2 can inhibit myocardial hypertrophy by enhancing the function of mitochondrial oxidative respiratory chain, regulating mitochondrial autophagy and AMPK/PINK1 signaling pathway.We intend to explore the effects of HINT2 on cardiac hypertrophy using pressure overload induced cardiac hypertrophy model on HINT2-knockout mice and HINT2-cardiac-specific transgenic mice,through analysis of cardiac function,gross heart,histology and molecular makers.We will further investigate myocardial energy metabolism,mitochondrial autophagy,AMPK and other signal transduction pathways to clear the underlying mechanisms of HINT2 in cardiac hypertrophy.In addition,cultured neonatal rat cardiomyocytes with silenced or overexpressed HINT2 will be used to observe the effects of HINT2 on Ang II-induced cardiomyocyte hypertrophy,apoptosis,mitochondrial autophagy and signal pathways.The study is designed to elucidate the role and underlying mechanisms of HINT2 in cardiac hypertrophy,and provide new experimental evidence and targets for clinical intervention in cardiac hypertrophy and heart failure.