基于MAPKs-线粒体信号crosstalk的环维黄杨星-D防治心肌细胞损伤的保护机制研究

The chronic heart failure(CHF) is the final pahtological results and death cause in the cardiovascular system diseases.Furhter research confirmed that the decrease of cardiac myocytes and abnormal of energy metabolism is key pathological process in the death of CHF.The mitochondrian,central organ of energy and one of initiation singal in apoptosis, was widely highlighted on the pathological change of structure and function.Accumulating evidents indicated that MAPKs are an important signals transduction pathway in eucaryon, which take part in many pathological process, even control key gene expression,which is the general pathway of cellular physiological reaction induced by extracellular signal.It is unclear of the relationship of mitochondrial system and MAPKs signal regualting cardiac myocytes apoptosis and energy metabolism. In our previous investigation and clinical application, cyclovirobuxine-D (CVB-D) can significantly ameliorate CHF and the mechanism involve in regualting energy metabolism and inhibiting cardiac myocytes apoptosis.At present research, CVB-D will be served as the targeted drug,the cardiac myocyte apoptosis will be reproduced by exposed to neuroendocrine factors including aldosterone and norepinephrine. The mitochindral system and MAPKs signal regulation crosstalk will be assayed in cardaic myocyte apoptosis with the inhibitor of MAPKs and mitochondrial function regulator which provide the novel theroetical breakthrough and experimental basis for prevention and treatment cardiac myocytes apoptosis. In further research, the focus will be on the intervention of CVB-D in cardaic myocytes apoptosis and the involved mechanism, and then explore the novel pharmacological effect of traditional Chinese medicine, and supplied new experimental basic and theoretical guide for clinical application.

心力衰竭是大多数心血管系统疾患病程演变的最终结果和主要死亡原因，心肌细胞的丢失及能量代谢的异常是心力衰竭导致死亡的关键病理因素。线粒体作为能量工厂及介导凋亡的器官，其结构与功能的变化成为当前研究的热点。MAPKs是真核生物信号传递网络中的重要途径之一，参与一系列生理病理过程甚至控制基因表达，是细胞外信号引起细胞生理反应的共同途径。线粒体系统与MAPK信号crosstalk对心肌细胞凋亡与能量代谢的调控迄今未见明确报道。临床及本实验室前期研究证实环维黄杨星D (CVB-D)对心力衰竭具有显著的改善作用，其机制与能量代谢及细胞凋亡相关。本项目以CVB-D为研究对象，建立心肌细胞凋亡模型，采用MAPKs 抑制剂及线粒体功能调控剂，分析MAPKs与线粒体信号的调控，为心肌细胞凋亡防治提供新理论和实验依据；探索CVB-D防治心力衰竭的作用及机制，为发掘中药新药理作用，拓宽临床应用提供实验与理论基础。

心力衰竭是大多数心血管系统疾患病程演变的最终结果和主要死亡原因，心肌细胞的丢失及能量代谢的异常是心力衰竭导致死亡的关键病理因素。线粒体作为能量工厂及介导凋亡的器官，其结构与功能的变化成为当前研究的热点。MAPKs是真核生物信号传递网络中的重要途径之一，参与一系列生理病理过程甚至控制基因表达，是细胞外信号引起细胞生理反应的共同途径。线粒体系统与MAPK信号crosstalk对心肌细胞凋亡与能量代谢的调控迄今未见明确报道。临床及本实验室前期研究证实环维黄杨星D (CVB-D)对心力衰竭具有显著的改善作用，其机制与能量代谢及细胞凋亡相关。.本项目以CVB-D为研究对象，建立醛固酮与高交感活性诱导心肌细胞损伤模型，以及醛固酮诱导大鼠实验性心力衰竭模型。采用MAPKs 抑制剂及线粒体功能调控剂，分析MAPKs与线粒体信号的调控，为心肌细胞凋亡防治提供新理论和实验依据；探索CVB-D防治心力衰竭的作用及机制，为发掘中药新药理作用，拓宽临床应用提供实验与理论基础。本研究首次采用形态学、生物化学与分子生物学的技术与方法，研究证实线粒体系统与MAPK信号crosstalk对心肌细胞凋亡与能量代谢的调控，ALD可诱导心肌细胞凋亡，作用机制与诱导心肌细胞p-P38和p-JNK蛋白表达上调，降低心肌细胞线粒体膜电位有关。MAPK信号通路与线粒体之间存在crosstalk，CVB-D调控两者之间的crosstalk改善ALD诱导心肌细胞凋亡作用。项目执行期间发表标准本项目资助的论文17篇，其中SCI论文7篇，核心期刊论文8篇。培养博士研究生2名，硕士研究生生8名。研究成果“心肌重塑病变新关键信号分子机制及药物干预作用”获得贵州省科技进步三等奖，项目负责人排名第一，获得发明专利2项，申请发明专利1项。