线粒体脂肪酸代谢对琥珀酸/线粒体ROS的调控机制作为心肺复苏后心肌氧化应激损伤防治靶点的研究

We confirmed that regulating mitochondrial respiratory chain electron transfer reduced mitochondrial ROS generation and alleviated myocardial oxidative stress injury after cardiopulmonary resuscitation. The abnormal electron leakage of mitochondrial respiratory chain is the main source of excessive mitochondrial ROS generation, but the upstream regulation mechanism remains unclear. Studies showed that abnormal succinate formation provided overloaded electronics to mitochondrial respiratory chain, leading to excessive ROS formation. The generation of succinate was related to mitochondrial fatty acid metabolism which was the main way of mitochondrial metabolism after ischemia /reperfusion. So, we thought whether myocardial succinate and mitochondrial ROS were decreased through regulating mitochondrial fatty acid metabolism after cardiopulmonary resuscitation? What is the mechanism? The preliminary experiment showed that myocardial succinate was significantly increased after cardiopulmonary resuscitation 1h, and inhibition of mitochondrial fatty acid metabolism evidently reduced the level of succinate and alleviated post-resuscitation myocardial oxidative stress injury. Based on the findings, we hypothesized that inhibition of mitochondrial fatty acid metabolism alleviated myocardial oxidative stress injury after cardiopulmonary resuscitation via reducing mitochondrial succinate / ROS formation. This study elucidates the mechanism of mitochondrial fatty acid metabolism regulating succinate / mitochondrial ROS in a rat model of cardiac arrest and the ischemia /reperfusion model of myocardial cell/mitochondria , in order to provide new way for prevention and treatment of myocardial oxidative stress injury after cardiopulmonary resuscitation.

我们已证实，调控线粒体呼吸链电子传递可减少心肺复苏后心肌线粒体ROS生成，改善心肌氧化应激损伤。线粒体呼吸链电子传递中异常的电子漏出是线粒体ROS生成的主要来源，但其上游调控机制仍不清楚。研究认为，琥珀酸的异常生成可为线粒体呼吸链提供大量的电子，形成过量ROS。而琥珀酸的增生与缺血再灌注后线粒体以脂肪酸代谢为主的代谢转变相关。那么，可否通过调控线粒体脂肪酸代谢，减少心肺复苏后心肌琥珀酸及线粒体ROS生成？机制是什么？预实验显示，大鼠心肺复苏后1h心肌琥珀酸水平显著升高；抑制线粒体脂肪酸代谢，可显著减少琥珀酸水平，改善心肌氧化应激损伤。由此我们提出假说：抑制线粒体脂肪酸代谢可通过减少琥珀酸/线粒体ROS生成，改善心肺复苏后心肌氧化应激损伤。本项目拟在大鼠心肺复苏模型、心肌细胞及线粒体水平上，阐明线粒体脂肪酸代谢对琥珀酸/线粒体ROS的调控机制，为心肺复苏后心肌氧化应激损伤的防治提供新的靶点。