基于miR-199a-5p/Sirt1/Sirt3轴调控的线粒体质量控制探讨芪苈强心胶囊干预CHF心肌能量代谢的作用机制

慢性心力衰竭（CHF）是严重威胁人类健康的重大疾病，已成为亟待解决的重大公共卫生问题。研究发现miR-199a-5p参与心肌细胞肥大、凋亡、心室重构，其靶基因Sirt1可介导线粒体质量控制（MQC）调控CHF心肌能量代谢，以MQC为作用靶点改善心肌能量代谢可能成为治疗CHF的有效策略。本项目以中医脉络学说为指导，认为CHF病机为“气阳虚乏、络瘀水停、络息心积”，制定“益气温阳、活血通络、利水消肿”的治法，以代表药物芪苈强心胶囊（QLQX）进行干预，从“整体动物-细胞-细胞器-分子”多层次出发，建立心梗后CHF大鼠模型和原代心肌细胞缺氧模型，采用基因载体转染和siRNA技术对miR-199a-5p/Sirt1进行基因过表达和沉默，探讨miR-199a-5p/Sirt1/Sirt3轴调控MQC参与心肌能量代谢及CHF的分子机制，并揭示QLQX基于此改善心肌细胞能量代谢、治疗CHF的作用机制。

Chronic hear failure (CHF) comes as serious threat to human health and has become a prioritized public health problem to be solved. Studies have shown that miR-199a-5p plays a part in cardiomyocyte hypertrophy, apoptosis and ventricular remolding and its target gene Sirt1 can mediate mitochondria quality control (MQC) to regulate CHF myocardial energy metabolism. With MQC used as an effect target to improve myocardial energy metabolism, it probably works effectively in the treatment of CHF. Following the vessel-collateral theory of traditional Chinese medicine, the project urged that CHF was pathologically caused by “deficiency of qi and yang, stasis of blood and water, masses developed with obstruction of collaterals”. Therefore, the treatment methods of “tonifying qi, warming yang, activating blood, dredging collaterals, promoting diuresis and eliminating edema” were developed. With QLQX, a representative medicine for the disease, used for intervention, the rat model of CHF post-myocardial infarction and primary cardiac myocyte hypoxia model, from the multi-level perspectives of entire animal-cell-organelle-molecule. Genophore transfection and siRNA technologies were used for gene overexpression and silence of miR-199a-5p/Sirt1. This way, it attempts to make clear the molecular mechanisms where miR-199a-5p/Sirt1/Sirt3 axis regulates MQC to play a part in myocardial energy metabolism and CHF. Moreover, it aims to ascertain the mode of action where OLOX improves, based on what has been mentioned just now, myocardial energy metabolism and inhibits CHF.