苦参碱调控Akt/eNOS信号通路抑制异丙肾上腺素致大鼠心脏肥厚的作用机制

Matrine, one of the active alkaloids extracted from Sephora alopecuroides L (an Hui medication), has been actively researched for its pleiotropic pharamcological effects. It is a compound of great interest because of its anti-cancer, anti-inflammatory and anti-arrhythmic properties. Furthermore, it has been shown to have cardioprotective effects on a variety of heart diseases, such as cardiac hypertrophy, but its mechanism remains unclear. To elucidate the cardioprotective effect and mechanism of action for matrine, experiments using a rat model will be conducted to obtain evidence-based data. A combination approach using pharmacology, molecular biology, histopathology and biochemistry will be utilized to perform the experiment. More specifically, the dose-response effect of matrine on cardiac structure and ventricular function will be measured on rats with isoprenaline-induced cardiac hypertrophy. Also, the molecular mechanisms of matrine on regulating the Akt/eNOS and RhoA/ROCK signaling are about to be monitored and the effect of matrine on the PRMT/ADMA/DDAH metabolism pathways will be investigated, which is involved in cardiac hypertrophy. Meantime, the holistic effect of matrine on isoprenaline-induced cardiac hypertrophy will be evaluated by looking at the pharmacokinetic and pharmacodynamic influence of matrine in the rat model. This study is expected to provide the foundational evidence for future clinical practice applications and explain the underlining mechanism of matrine's cardioprotective property.

苦参碱是从宁夏特色回药材-豆科槐属植物苦豆子中提取的生物碱之一，具有抗肿瘤、抗炎和抗心律失常等多种药理作用，尤其是对心血管系统具有多种显著保护作用。目前国内外研究表明：苦参碱对心脏肥厚具有抑制作用，但其作用及作用机制尚未完全阐明。本研究旨在通过异丙肾上腺素致大鼠心脏肥厚模型的建立，综合采用药理学、分子生物学、病理学和生物化学等方法与技术手段，观察不同剂量的苦参碱对心脏肥厚大鼠心脏和功能的保护作用；重点探讨苦参碱对以Akt/eNOS信号转导通路为主的上下游各主要调控分子的干预作用；并对影响eNOS稳定性的RhoA/ROCK通路和与之竞争底物的ADMA及其代谢酶PRMT与DDAH含量的变化进行检测分析。同时，从整体动物水平考察苦参碱对异丙肾上腺素在大鼠体内药动学的影响。以期阐明苦参碱对心脏肥厚的抑制作用及其作用的机制，为进一步苦参碱的临床应用提供实验依据。

苦参碱是从宁夏特色回药材-豆科槐属植物苦豆子中提取的生物碱之一，具有抗肿瘤、抗炎和抗心律失常等多种药理作用，尤其是对心血管系统具有多种显著保护作用。国内外研究表明：苦参碱对心脏肥厚具有抑制作用，但其作用及作用机制尚未完全阐明。本研究通过建立异丙肾上腺素致大鼠心脏肥厚模型，综合采用药理学、分子生物学、病理学和生物化学等方法与技术手段，观察不同剂量的苦参碱对心脏肥厚大鼠心脏和功能的保护作用；重点探讨了苦参碱对Akt/eNOS信号转导通路与RhoA/ROCK信号通路上下游因子的调控作用；并对影响eNOS稳定性的RhoA/ROCK通路和与之竞争底物的ADMA及其心肌损伤标志酶cTn-I与ADMA含量的变化进行了检测分析。同时，在整体动物水平考察苦参碱在心脏肥厚大鼠血浆和组织中药动学特征。阐述了苦参碱对心脏肥厚的抑制作用及其作用的机制，为进一步苦参碱的临床应用提供实验依据。项目资助发表SCI论文1篇，核心论文4篇，待发表论文2篇。培养硕士生5名，其中4名已经取得硕士学位，1名在读。