Notch-1在心肌缺血再灌注损伤中的作用与机制研究

本研究拟通过建立小鼠心肌梗死(MI)及缺血再灌注(MIRI)模型和SD乳鼠心肌细胞缺氧及缺氧复氧模型，探索Notch-1及其下游信号分子Hes-1和RBP-Jκ在心肌缺血及再灌注期间的差异表达对心功能的影响及其机制；分别采用腺相关病毒载体和RNA干扰技术实现Notch-1过表达及基因沉默，以研究心肌缺血及再灌注期间Notch-1表达上调与下调对心肌细胞凋亡及梗死面积的影响，并探究Notch-1激活抑制心肌再灌注期间细胞凋亡的可能机制：活化的Notch-1通过增加再灌注损伤营救激酶(RISK)的表达，抑制再灌注早期活性氧簇(ROS)爆发诱导的线粒体通透转换孔(mPTP)开放。揭示Notch-1在心肌缺血再灌注过程中的作用及机制，有望为缺血性心脏病和心肌缺血再灌注损伤的临床防治提供新的靶点。

Mitochondrial permeability transition pore(mPTP) plays a critical role in apoptosis.It has been found by our research team that the level of Notch-1 is upregulated during ischemia (hypoxia) while downregulated during reperfusion (reoxygenation) on the basis of myocardial ischemia reperfusion model and myocardial cell hypoxia and reoxygenation model.We speculate that Notch-1 activation inhibits mPTP opening mediated myocardiocyte apoptosis by upregulating RISK expression and downregulating ROS level, hence attenuates myocardial ischemia reperfusion injury.Tools in this study include mouse models of myocardial infarction(MI), myocardial reperfusion injury(MIRI) and cell models of hypoxia, reoxygenation. Notch-1 activation during reperfusion may be a novel and preferable approach in the treatment of myocardial ischemia reperfusion injury in the clinical setting.