盐酸戊乙奎醚预处理和后处理对心肌缺血再灌注损伤保护机制及其线粒体信号通路的研究

项目名称： 盐酸戊乙奎醚预处理和后处理对心肌缺血再灌注损伤保护机制及其线粒体信号通路的研究

项目编号： No.81471902

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 马骏

作者单位： 首都医科大学

项目金额： 80万元

中文摘要： 心肌缺血导致的心肌损伤是心血管疾病的主要病因，尽早恢复心肌灌注是治疗关键。然而，当心肌组织重新获得血液供应时，却存在缺血-再灌注损伤（IRI）。IRI一直是心肌缺血治疗中难以解决的问题。 线粒体是细胞生命活动的控制中心。我们的前期动物实验发现盐酸戊乙奎醚(PHC)1mg/kg预处理可减少线粒体外膜通透性的增加，具有IRI保护作用，但其确切机制以及PHC预处理对IRI保护的最佳剂量，PHC后处理是否也具有IRI保护的作用，仍需进行进一步的研究。 在该研究中我们将首先经过离体心肌细胞缺氧/复氧损伤模型研究PHC能否通过调控线粒体途径对缺氧/复氧损伤的心肌细胞起保护作用，以及探索所需的剂量和应用时机；然后再经大鼠心肌缺血再灌注损伤模型进行在体实验进一步研究和证实，以期为临床治疗心肌缺血再灌注损伤找到新的干预环节及治疗靶点提供依据。

中文关键词： 心肌缺血-再灌注损伤；线粒体膜通透性；盐酸戊乙奎醚；预处理；后处理

英文摘要： Cardiac damage caused by myocardial ischemia is the main cause of cardiovascular disease. Restore myocardial perfusion as soon as possible was the key point for the clinic treatment. Recent study found that myocardial ischemia with inadequate oxygen supply followed by successful reperfusion initiates a wide and complex array of inflammatory responses that may both aggravate myocardial injury as well as induce impairment of remote organ function, which is called ischemia-reperfusion injury (IRI). How to attenuate IRI have been becoming the main problems in the treatment of myocardial ischemia. The mitochondria are the control center of cell life activities. It is not only the center of the cell respiration chain and oxidative phosphorylation, but also the regulation center of cell apoptosis. When promoting apoptosis factor act on the mitochondria, the mitochondria permeability transition pore excessively open, which results in the decrease of mitochondrial membrane potential, apoptosis perform factor cytochrome C released from mitochondria to cytoplasm, then cascade of apoptosis started. Penehyelidine hydrochloride (PHC) is a new selective cholinergic antagonist found by China. Clinical studies have found that it has myocardial protection, anti-inflammatory, cell membrane stability, and improve microcirculation, but its mechanism is not clear. In our previous study, we have found that pre-conditioning with 1 mg/kg PHC in IRI rats may decrease the myocardial ischemia-reperfusion injury through the modulation of mitochondria membrane permeability. But it still need further investigate to find the most suitable dosage for the myocardial protection and whether the PHC post-conditioning also have the effection of myocardial protection. In this study, we'll examine the anti-myocardial ischemia-reperfusion injury by PHC pre/post-conditioning in anoxia/reoxygenation mycardial cells firstly, and discuss their mitochondria regulatory mechanism, and then to confirm in IRI rats. Our aim is to find a new intervention method for clinical application of myocardial ischemia-reperfusion injury.

英文关键词： Myocardial ischemia-reperfusion injury;Mitochondria membrane permeability;Penehyelidine hydrochloride;Pre-conditioning;Post-conditioning