基于mTORC1-线粒体自噬途径探讨益气温阳活血利水方防治心衰的机制

The dysfunction of mitophagy was the main pathological changes of cardiomyocytes during heart failure. The down-regulation of mTORC1 expression reduced cardiomyocyte hypertrophy and ischemic injure, protected the cardiomyocytes. The relationship of mTORC1 and mitophagy was not clear in heart failure. Preclinical studies had shown that formula for reinforcing qi, warming yang, activating blood and promoting diuresis could improve the symptoms of heart failure, quality of life and prognosis in patient; regulate the mitochondrial function, down - regulate the expression of mTOR, up - regulate the expression of autophagy protein in heart failure rats. In this study, we would investigate the relationship of mTORC1 and mitophagy proteins (PINK / Parkin, BNIP3 / NIX, FUNDC1) during the model of heart failure. The effect of the formula for reinforcing qi, warming yang, activating blood and promoting diuresis on the model of heart failure was observed. Through the RNA interference technology, it was helpful to investigate whether The effect of the formula for reinforcing qi, warming yang, activating blood and promoting diuresis on the model of heart failure was associated with the pathway from mTORC1- mitophagy aspect. In summary, it was helpful to explain the formula for reinforcing qi, warming yang, activating blood and promoting diuresis to prevent heart failure.

线粒体自噬功能失调是心衰过程中心肌细胞的主要病理表现。mTORC1下调可减少心肌肥厚，保护心肌细胞，减少缺血性损伤。但是mTORC1与线粒体自噬在心衰中的作用并不清楚。前期研究表明益气温阳活血利水方可改善患者症状、生存质量、预后；调节心衰大鼠线粒体功能，下调mTOR、上调自噬蛋白的表达。本研究主要通过建立心肌细胞心衰模型，观察线粒体自噬的改变，探讨mTORC1与线粒体自噬调节蛋白（PINK/Parkin、BNIP3/NIX、FUNDC1）关系，阐述益气温阳活血利水方对心衰模型作用。采用RNA干扰技术实现心衰模型mTORC1的沉默，探讨益气温阳活血利水方对心衰模型的作用是否与mTORC1调节线粒体自噬有关，阐述益气活血温阳利水方防治心衰的科学内涵。

线粒体自噬功能失调是心衰过程中心肌细胞的主要病理表现。mTORC1下调可减少心肌肥厚，保护心肌细胞，减少缺血性损伤。但是mTORC1与线粒体自噬在心衰中的作用并不清楚。本研究发现心肌细胞心衰模型中线粒体自噬增多，自噬标记蛋白（Beclin1）、自噬调节蛋白（PINK/Parkin、BNIP3/NIX、FUNDC1）、mTOR表达增多；与模型组相比，益气温阳活血利水方干预心肌细胞心衰模型后线粒体边界较清晰，肿胀缓解，空泡明显减少，ATP 含量明显增加，ROS 含量减少，自噬小体数量减少，自噬标记蛋白（Beclin1）、自噬调节蛋白（PINK/Parkin、BNIP3/NIX、FUNDC1）、mTOR表达减少。通过雷帕霉素阻断mTORC1的表达，与模型组相比，雷帕霉素组、雷帕霉素+益气温阳活血利水方(400mg/L)组自噬标记蛋白（Beclin1）、自噬调节蛋白（BNIP3/NIX、FUNDC1）表达明显增多，自噬小体的含量增多，表明益气温阳活血利水方对心衰模型的作用与mTORC1下调后促进（BNIP3/NIX、FUNDC1）的表达，引起线粒体自噬增多密切相关，阐述益气活血温阳利水方防治心衰的科学内涵。