IPC通过CFTR调节内质网应激-线粒体自噬稳态改善心肌缺血再灌损伤的实验研究

Ischemic preconditioning significantly reduced the extent of myocardial infarction caused by subsequent ischemia reperfusion injury, whereas the mechanism remained unclear. Recent studies have been showed that CFTR played a key role in IPC protection on myocardial reduction of IRI. Our preliminary study found that ischemia preconditioning enhanced CFTR expression which decreased the ROS production during ischemia repferfusion injury. Meanwhile, the decreased ROS reduced mPTP opening, and inhibited endoplasmic reticulum stress as well as enhanced mitophagy during ischemia repferfusion injury. Thus, we hypothesize that increased CFTR phosphorylation expression resulting in reducing mPTP open is the crucial role to restore endoplasmic reticulum stress and mitophagy homeostasis. The project intends to use Isolated heart perfusion model and primary cardiomyocytes to exprlore the molecular mechanisms of inactivation of CFTR Prevents Ischemic Preconditioning from ischemia reperfusion injury by regulating endoplasmic reticulum stress-mitophagy homeostasis. The proposed studies may provide novel therapies for improving myocardial ischemia repferfusion injury.

缺血预处理（IPC）可以显著减少随后的缺血再灌引起的心肌梗死面积，但机制不明确。新近研究发现CFTR在IPC保护心肌减少IRI时起关键性作用。我们预实验发现囊性纤维化跨膜传导调节蛋白（CFTR）在IPC时表达增加并减少了心肌IRI时活性氧（ROS）生成，同时，ROS降低可以减少线粒体通透性转换孔（mPTP）通道开放，抑制内质网应激并能提高线粒体自噬，从而减少IRI。我们推测增加CFTR表达进而减少mPTP开放是恢复内质网应激-线粒体自噬稳态减少IRI的关键。本项目拟在离体心脏灌流模型和原代细胞上探索IPC通过CFTR调节内质网应激-线粒体自噬稳态改善IRI的分子机制，为改善心肌IRI提供新思路。

缺血预处理（IPC）可以显著减少随后的缺血再灌引起的心肌梗死面积，但机制不明确。本研究发现CFTR在IPC保护心肌减少IRI时起关键性作用。IPC诱导下CFTR蛋白表达增高，减少了ROS释放，进一步减少了内质网应激，进而减少了mPTP的开放，增加了线粒体自噬，降低心肌缺血再灌损伤。同时本项目还通过CFTR心肌特异性基因敲除小鼠论证了，敲除CFTR后，IPC保护作用消失，ROS升高，内质网应激增加，mPTP开放增加，线粒体自噬减少，线粒体病态数量增加。本项目详细阐明了，IPC通过CFTR介导的ROS降低对内质网应激-线粒体自噬稳态的影响，进而改善心肌IRI的详细机制，为临床开发心肌IRI保护的药物提供新靶点，临床治疗提供理论基础和实用价值。