Sirt5去琥珀酰化在急性心脏缺血缺氧中的作用及机制研究

急性心肌梗死是危害我国人民健康的重要疾病，不论治疗如何及时，心肌在冠脉闭塞后仍会受到不可逆的损伤。文献报道提示赖氨酸琥珀酰化修饰增加会加重急性心脏缺血缺氧损伤，但具体机制不明。我们的前期研究首次发现：人类及小鼠血浆中均存在琥珀酰化修饰的蛋白，急性心肌梗死患者或者小鼠血浆中蛋白的琥珀酰化修饰较健康志愿者或者假手术小鼠显著减少；急性心肌梗死小鼠的心脏中Sirt5的表达水平较假手术组明显升高。我们假设：Sirt5去琥珀酰化修饰可能在急性心肌梗死中发挥保护作用，急性心脏缺血缺氧可能通过PGC-1α/PPAR-γ通路上调Sirt5的表达，使心肌细胞能量代谢关键蛋白去琥珀酰化修饰，改变线粒体呼吸体的空间构型，加强线粒体能量代谢，从而发挥保护作用。我们拟通过本课题明确：急性缺血缺氧的心脏及缺氧的心肌细胞中琥珀酰化修饰受影响的蛋白及功能；急性缺血缺氧的心脏中琥珀酰化修饰的调控机制及潜在的治疗靶点。

Acute myocardial infarction(AMI) is the leading cause of death in our country, no matter how soon the rescue is, coronary occlusion results in irreversible ischemic and anoxic myocardial injury. Research has shown that increase of lysine succinylation leads to aggravation of acute ischemic and anoxic myocardial injury, but the mechanism remains unknown. Our preliminary results showed that succinylated protein was found in human and mice serum, and the relative abundance of succinylated serum protein was significantly reduced in AMI human and mice, compared with healthy volunteer and sham surgery mice; Sirt5 expression was elevated in the heart of AMI mice compared with sham surgery mice. We hypothesize: Sirt5 de-succinylation may have protective role in AMI, in that acute ischemia and hypoxia may up-regulate Sirt5 through PGC-1α/PPAR-γ pathway, and de-succinylate key mitochondrial proteins regulating myocardial energy metabolism, thus change the structure of mitochondrial respirasome, promote energy generation and protect the heart from ischemia and hypoxia. We sought to elucidate: The function of succinylated proteins in acute ischemic and anoxic myocardium, as well as cardiomyocytes cultured in hypoxia; The mechanism and potential treatment target of succinylation in acute ischemic and anoxic myocardium.