基于ERs-PI3K通路的三七皂苷类成分防治心肌缺血再灌注损伤的分子机理研究

项目名称： 基于ERs-PI3K通路的三七皂苷类成分防治心肌缺血再灌注损伤的分子机理研究

项目编号： No.81503289

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李光

作者单位： 中国医学科学院药用植物研究所

项目金额： 17万元

中文摘要： 心肌缺血再灌注损伤（MIRI）已成为临床冠心病患者获得再灌注治疗最佳疗效的主要障碍，细胞凋亡是MIRI产生的关键环节，PI3K通路是参与细胞凋亡最重要的信号通路，雌激素受体（ERs）激活后可通过PI3K通路调控下游通路达到治疗多种疾病的目的。前期研究表明具有雌激素样活性的三七皂苷类成分具有很好的抗MIRI作用，课题组前期已证实三七皂苷类成分能够调控ERs-PI3K通路及下游通路抑制细胞凋亡，由此提出假说：三七皂苷通过调控ERs-PI3K通路抑制细胞凋亡保护MIRI。为验证该假说，本项目拟通过多种生物学技术考察PNS对MIRI模型ERs-PI3K通路中ER、p85α、Ras、AKt等关键蛋白、基因表达的影响，并应用靶点拮抗剂进行“功能缺失”验证，旨在从分子层面阐明三七皂苷抗MIRI的机理，为其深入开发提供理论依据，另一方面也丰富了MIRI的致病理论，为确认MIRI新的治疗靶点提供参考。

中文关键词： 三七皂苷成分；心肌缺血再灌注损伤；雌激素受体；PI3K通路；分子机制

英文摘要： Reperfusion is the most effective treatment for acute myocardial infarction, markedly reducing mortality and morbidity. Reperfusion however induces necrotic and apoptotic damages to cardiomyocytes, that were viable prior to reperfusion, a process called Myocardial Ischemia/Reperfusion Injury (MI/RI). Over the past 30 years, hundreds of experimental interventions (both pharmacologic and nonpharmacologic) have been reported to protect the ischemic myocardium in experimental animals; however, with the exception of early reperfusion, none has been translated into clinical practice. The population-based survey assessed men have about twice the total incidence of morbidity and mortality of women, and the sex gap in morbidity tends to diminish after age 45 years. Several studies suggested that estrogen had the protective effect for MIRI, and most of researchers believed that apoptosis was the most important component for MIRI, and estrogen receptor (ER) can regulate PI3K signaling cascade, which was the most important signaling pathways involved in apoptosis. Those suggested that one of the possible mechanisms of estrogen anti MIRI was the inhibition of apoptosis by ERs-PI3K signaling cascade. Previous studies had shown that the total saponins of Pnanxnotoginseng (PNS), one of the phytoestrogen, which could regulate the PI3K signaling cascade in cell, had beneficial protective effect for MIRI. Accordingly, we propose the hypothesis that one of the probability mechanisms for the protective effects on MIRI-induced apoptosis by PNS is through ERs-PI3K signaling cascade. By establishing the rat model of myocardial MIRI, the hypoxia/reoxygenation myocardial cell model, and the gene and protein over-expression or expression inhibited myocardial cell model by transfected with Ers, PI3K, and eNOS inhibitor, the intervention effects of PNS is observed at molecular, cellular, and animal levels. This study could provide a new approach and theoretical basis for phytoestrogen composition in prevention and treatment of MIRI.

英文关键词： saponins of Pnanx notoginseng;MIRI;ER;PI3K siganling cascade;molecular mechanisms