基于线粒体稳态调控研究参芪苈心方对心衰大鼠心肌能量代谢的干预作用和机制

Myocardial energy metabolism disorder is an important pathophysiological mechanism of heart failure. Mitochondria are the regulatory centers of energy metabolism. Maintaining the relative stability of mitochondria number, morphology and function is the key to myocardial energy metabolism. Fusion-cleavage, autophagy and biosynthesis are the core of mitochondrial quality control and an important mechanism for maintaining mitochondrial homeostasis. Based on Yiqi Huoxue Lishui treatment, the effect of Shenqilixin recipe in the treatment of heart failure significantly. In the early stage, it has been proved that reduces myocardial fatty acid oxidation, increases glucose metabolism, protects mitochondrial membrane potential, and improves cardiac function. Based on that, it is proposed that Shenqilixin recipe may improve the myocardial energy metabolism and regulate the hypothesis of cardiac function by regulating the quality control system of mitochondrial homeostasis.It is proposed to use targeted metabolomics technology to accurately assess the characteristics of myocardial energy metabolism under heart failure.Multiple pattern recognition methods are mutually validated, combined with metabolic pathway analysis, screening for significantly different metabolites, and determining the target of Shenqilixin recipe regulation energy metabolism.From the aspects of mitochondrial mass, membrane potential, fusion-cleavage and biosynthesis of key gene protein expression, mitochondrial autophagy activity, etc, explore the mechanism of myocardial mitochondrial homeostasis and energy metabolism in rats with heart failure at subcellular and molecular levels,to enrich the scientific connotation of the method of invigorating qi, activating blood circulation and regulating water in the treatment of heart failure.

心肌能量代谢障碍是心衰重要的病理生理机制。线粒体是能量代谢的调控中心。维持线粒体数量、形态和功能相对稳定是心肌能量代谢的关键。融合-分裂、自噬与生物合成是线粒体质量控制体系的核心环节，也是维持线粒体稳态的重要机制。益气活血利水法组方参芪苈心方治疗心衰临床效果显著。在前期已证实该方具有降低心肌脂肪酸氧化、提高葡萄糖代谢、保护线粒体膜电位、改善心功能作用的基础上，提出参芪苈心方可能通过调节线粒体稳态质量控制体系，优化心肌能量代谢，进而改善心功能的假说。拟用靶向代谢组学技术，精确评估心衰状态下心肌能量代谢特征及参芪苈心方干预效应，定性定量分析识别差异代谢物，确定其调节能量代谢的靶点。从线粒体形态结构、膜电位水平、调控融合-分裂及生物合成的关键基因蛋白表达、线粒体自噬活性等方面，在亚细胞和分子水平探索参芪苈心方干预心衰大鼠心肌线粒体稳态失衡调节能量代谢的机制，丰富益气活血利水法治疗心衰的科学内涵。

心肌能量代谢障碍是心衰重要的病理生理机制。线粒体是能量代谢的调控中心。维持线粒体数量、形态和功能相对稳定是心肌能量代谢的关键。融合-分裂、自噬与生物合成是线粒体质量控制体系的核心环节，也是维持线粒体稳态的重要机制。益气活血利水法组方参芪苈心方治疗心衰临床效果显著。在前期已证实该方具有降低心肌脂肪酸氧化、提高葡萄糖代谢、保护线粒体膜电位、改善心功能作用的基础上，提出参芪苈心方可能通过调节线粒体稳态质量控制体系，优化心肌能量代谢，进而改善心功能的假说。从线粒体形态结构、膜电位水平、调控融合-分裂及生物合成的关键基因蛋白表达、线粒体自噬活性等方面，在亚细胞和分子水平探索参芪苈心方干预心衰大鼠心肌线粒体稳态失衡调节能量代谢的机制，丰富益气活血利水法治疗心衰的科学内涵。.参芪苈心方干预心力衰竭大鼠心肌代谢组学研究方面，共筛选出28个潜在差异代谢物，所属代谢通路主要涉及三羧酸循环、天冬氨酸和谷氨酸代谢、组氨酸代谢、谷氨酸代谢、精氨酸生物合成、生物素代谢等能量代谢相关通路。机制研究结果表明参芪苈心方能够明显改善心力衰竭大鼠心肌细胞和线粒体的超微结构，降低心肌细胞线粒体自噬水平，具有保护心肌的作用；参芪苈心方能够提高CHF大鼠心肌细胞线粒体膜电位水平， 促进心力衰竭大鼠心肌PGC-1α表达、上调线粒体融合蛋白Mfn1、Mfn2、OPA1，下调线粒体分裂蛋白Drp1和Fis1，能有效平衡心力衰竭大鼠心肌组织中PGC-1α介导的线粒体分裂和融合，调控心力衰竭大鼠心肌线粒体动力学；参芪苈心方降低PINK1和Parkin蛋白的表达水平以及LC3Ⅱ/LC3Ⅰ的比值，上调p62蛋白的表达水平，抑制PINK1/Parkin通路介导的线粒体自噬，改善心力衰竭大鼠心肌线粒体自噬过度的状态，促进线粒体稳态调控，进而调节能量代谢发挥心力衰竭大鼠心肌保护作用。细胞实验也表明OGD/R诱导的心肌细胞中PGC-1α、Mfn2和Opa1的表达减少，而Drp1和Fis1的表达增加，参芪苈心方含药血清能有效促进OGD/R诱导的心肌细胞PGC-1α、Mfn2和Opa1的表达，抑制Drp1和Fis1的表达。.研究成果发表SCI论文2篇（第一作者）。