Sirt1-Sirt3轴性互动调控线粒体质量动态平衡对心肌缺血再灌注损伤的保护机制研究

缺血性心脏病严重威胁人类生命健康，而心肌缺血再灌注损伤（MIRI）则是严重影响其手术疗效的关键难题。研究证实维持线粒体质量动态平衡与内稳态是防治MIRI的关键；Sirt1和Sirt3双重调控线粒体质量，但它们如何轴性互动调控线粒体质量和内稳态，尚无研究报道。我们前期研究发现激活Sirt1可保护MIRI，过表达Sirt1/Sirt3可调控线粒体生物合成，并且特异性Sirt1/Sirt3转基因可抵抗MIRI。据此我们提出假说：Sirt1与Sirt3可轴性互动调控线粒体质量，维持线粒体内稳态及能量平衡，保护MIRI。本研究拟通过心肌细胞缺氧复氧模型和MIRI动物模型，采用siRNA沉默干扰、基因过表达转染等分子生物学技术，以Sirt1和Sirt3为干预靶点，从在体、离体和细胞水平，探寻Sirt1-Sirt3轴性交互调控线粒体质量平衡和内稳态的分子机制，为有效防治MIRI提供理论依据和新靶点。

Ischemic heart disease seriously threatens human life and health, and myocardial ischemia-reperfusion injury (MIRI) is a key problem that seriously affects the efficacy of its surgery. Studies have confirmed that maintaining the dynamic balance of mitochondrial mass and the homeostasis of mitochondria is the key to preventing and treating MIRI; Sirt1 and Sirt3 dually regulate mitochondrial mass, but how they interact to regulate mitochondrial mass and homeostasis has not been reported. Our previous research found that activation of Sirt1 can protect MIRI, overexpression of Sirt1/Sirt3 can regulate mitochondrial biosynthesis, and specific Sirt1/Sirt3 transgene can resist MIRI. Based on these, we propose a hypothesis: Sirt1 and Sirt3 can interactively regulate mitochondrial mass, maintain mitochondrial homeostasis and energy balance, and protect MIRI. In this study, SIRT1 and SIRT3 will be used as intervention targets to explore the molecular mechanism of sirt1-sirt3 axis interactive regulation of the mass balance and homeostasis of mitochondria at the level of in vivo, in vitro and in cells by using siRNA silencing interference, gene over expression transfection and other molecular biological techniques, so as to provide theoretical basis and new targets for effective prevention and treatment of MIRI.