淫羊藿苷抑制内质网应激改善大鼠缺血性心力衰竭心功能的研究

Cardiomyocytes apoptosis and calcium homeostasis disorder induced by severe endoplasmic reticulum stress are the important molecular mechanism of heart failure, thus regulating endoplasmic reticulum stress become a novel prevention and therapeutic target in heart failure. Icariin, a flavonoid isolated from Chinese medicinal herb, Epimedium brevicornu Maxim, has been demonstrated to have a wide range of pharmacological and biological activities, including estrogenic activity, antioxidant effects, anti-tumor activity, immunoregulation, neuroprotection and improving sexual function. Recent studies suggested that icariin could increase the expression of glucose regulation protein 78(GRP78), a gene in rabbit aortic vascular smooth muscle cells to prevent atherosclerosis. Furthermore, icariin significantly attenuated cardiomyocyte apoptosis, ameliorated left ventricular dysfunction and cardiac remodeling in the heart failure model induced by isoproterenol. However, the underlying mechanisms remain unclear. Our preliminary data showed that icariin could increase cell viability and decrease cell apoptosis by inhibiting endoplasmic reticulum stress. So we hypothesized that icariin could ameliorate cardiac function in ischemic heart failure and its mechanisms may be assoaciated with inbitibing endoplasmic reticulum. In this study, we aim (1) to investigate whether icariin has protective effects on cell injury induced by chemical ERS inducer and oxygen/glucose deprivation. Real time PCR and Western blot methods are used to observe the expression of ERS markers protein; siRNA and gene transfection techniques are used to identify the target of icaiin and to clarify the signalling pathway of regulation ERS. (2) to explore whether icariin improve cardiac function and whether its mechanisms are associated with inhibiting ERS by using a well established model of ischemic heart failure via left anterior descending artery(LAD) ligation. The studies will shed light on understanding of the molecular mechanism of icariin and provide theoretical basis for clinical application of ICA.

内质网应激导致心肌细胞凋亡、钙稳态失衡是心力衰竭发生的重要分子机制，调控内质网应激成为防治心功能下降的新靶点。淫羊藿苷(ICA)上调家兔主动脉血管平滑肌GRP78基因表达，防治动脉粥样硬化；改善异丙肾上腺素诱导心力衰竭模型的心功能，但是其机理不清。我室预实验结果研究表明：淫羊藿苷(ICA)降低内质网应激介导的心肌细胞凋亡，提高细胞存活率,所以推测其可能通过调控内质网应应激，改善缺血性心衰心功能。我们将采用内质网应激诱导剂或缺氧/缺糖损伤心肌细胞，通过流式、免疫荧光结合共聚焦与WB技术、siRNA CHOP和转染高表达CHOP质粒，研究淫羊藿苷是否对内质网应激有调控作用，明确其调控内质网应激的信号通路；在整体动物水平，建立缺血性心衰模型，研究ICA是否具有改善心功能的作用及其与内质网应激的相关关系。本课题将揭示ICA治疗缺血性心衰的作用及机制，为日后ICA应用于临床提供理论依据。