能量代谢紊乱是心力衰竭心功能下降和心室重构最主要的因素，过氧化物酶体增殖物激活受体γ 辅激活因子-1α（PGC-1α）在心肌能量代谢包括原料的利用、氧化磷酸化、线粒体的生物合成及脂肪氧化方面起着关键调节作用。淫羊藿苷（ICA）能改善异丙肾上腺素或缺血诱导心力衰竭的心功能，但其对能量代谢重构的作用不清楚。研究表明ICA促进胚胎干细胞向心肌细胞分化，并促进PGC-1α，PPARα和NRF-1的表达，所以推测ICA可能通过PGC-1α改善缺血性心衰的心肌能量重构。我们将采用采用缺氧/缺糖损伤心肌细胞能量代谢，通过流式、WB 和免疫组化和敲除和过表达PGC-1α，研究ICA是否改善能量代谢及其与PGC-1α的关系；进一步在整体动物上采用缺血性心衰模型研究ICA对心肌能量代谢的作用及其ICA调节PGC-1α的信号通路。本课题将揭示ICA治疗缺血性心衰的作用机制，为日后ICA应用于临床提供理论依据。

Metabolic and functional disturbances are the key factors when common diseases such as hypertension and diabete develop into heart failure, The PPARγ coactivator-1 (PGC-1α) play a key role in regulating genes involved in myocardial fuel metabolism and cardiac function. So the PGC-1α signaling pathway is a plausible candidate therapeutic target for novel therapeutics aimed at reversing the energy metabolic disturbances that contribute to heart failure. Icariin, a flavonoid isolated from Chinese medicinal herb, have a wide range of pharmacological and biological activities , including antioxidant effects, anti-tumor activity, immunoregulation , neuroprotection. Recent studies showed that icaiin could reduce cardiomyocyte apoptosis ,ameliorated heart fuction in the heart failure of animal model induced by isopreterenol and left anterior descending artery(LAD)ligation. But the machenism is not clear. Icariin showed a significant effect on murine embryonic stem (ES) cells. It promoted cell differentiation into beating cardiomyocytes and increased the expression of PGC-1α, PPARα and NRF-1,that showed icaiin could upregulate PGC-1α and promote energy metabolism,so we hypothesized that icaiin could ameliorate metabolic remodeling. In this study, we aim 1)to investigate the effect of icaiin on metabolism of remodeling in the oxgen /glucose deprivation and the relationship with PGC-1α. Real tiome PCR, immunohistochemical,western blot etal are used to determine the myocardial metabolism and the expression of PGC-1α and its up-down signalling pathway, then siRNA PGC-1α and high expresion of PGC-1α techniques are used to identify the target of icaiin and to clarify the signalling pathway; 2) to explore the effect of icariin on the metabolism of myocardial of heart failure induced by LAD ligated model and to determine the pathway. The studies will shed light on understanding of the mechanism of incariin and provide theoretical basis for clinical aplication in the future

心力衰竭（heart failure，HF）是各种心血管疾病的终末阶段，也是心血管疾病致死的最主要和最直接原因，能量代谢贯穿心力衰竭的全过程，也是心力衰竭发生、发展的重要因素之一，线粒体生物合成（Mitochondrial biogenesis）是维护和修复线粒体结构的生理活动，是介导核基因对线粒体基因及蛋白表达调控的生要桥梁，PGC-1α在能量平衡、线粒体氧化代谢、热量控制及糖、脂代谢中发挥重要的作用。淫羊藿苷(Icariin,ICA)是从淫羊藿植物中提取的主要活性成分，是一种黄酮醇苷化合物，前期研究发现淫羊藿苷因其抗氧化性，可降低内质网应激诱导的细胞凋亡，对异丙肾上腺素诱导的心力衰竭的心功能有改善作用，但淫羊藿苷对心力衰竭的心功能改善作用是否与能量重构有关还不清楚。本研究利用H9c2细胞，建立缺氧/缺糖模型（oxygen glucose deprivation) 模拟心肌缺血，采用10（低剂量）、20（中剂量）、40µM ICA（高剂量）预处理1h,后缺氧缺糖处理6h,研究发现中、高剂量组显著增加缺氧/缺糖诱导损伤的心肌细胞存活率，并具浓度依赖性，LDH漏出量减少，SOD活性增加，采用Hoechst33258检测细胞的凋亡率，发现其淫羊藿苷高浓度可降低其凋亡率; ROS主要来源于线粒体有氧呼吸和代谢过程，研究发现淫羊藿苷可降低ROS的产生；进一步研究线粒体数目与膜电位，淫羊藿苷高剂量组降低缺氧/缺糖诱导线粒体数目的减少，增加线粒体体膜电位，增加线粒体功能，从而使ATP产生增加。进一步研究发现淫羊藿苷上调PGC-1α、NRF-1、NRF-2通路蛋白的表达；在缺血心力衰竭大鼠在体模型上发现淫羊藿苷降低缺血性心衰的LVEDP，增加dp/dtmax,降低左心室指数，降低心肌组织的凋亡，上调PGC-1α。总之，本研究在离体与在体缺血模型的研究发现：①中、高剂量淫羊藿苷可减轻缺血诱导的细胞损伤；② 高剂量淫羊藿苷能改善缺血诱导能量代谢紊乱，增加线粒体的数量与功能；③其改善能量代谢与其上调PGC-1α/NRF-1/NRF-2通路有关。