Objective: To investigate the effect of Fuyu Decoction on ventricular remodeling and its association with AMPK/mTOR pathway-mediated autophagy in rats with heart failure.
Methods: Thirty male Wistar rat models of heart failure induced by ligation of the left anterior descending coronary artery were divided into model group, Fuyu Decoction treatment group, Fuyu Decoction treatment +AMPK agonist group (n=10), with another 10 rats receiving sham operation as the Sham group. After 8 weeks of drug intervention, the changes of ventricular function and ventricular remodeling indexs of the rats were assessed. TTC staining was used to detect the myocardial infarction area, and HE and Masson staining were used to observe the pathological changes in the myocardial tissue. Western blotting was performed to detect the protein expressions of p-AMPK, p-mTOR, LC3-II, Beclin1 and p62 in the myocardial tissue.
Results: Compared with the sham-operated rats, the rat models of heart failure showed significantly increased left ventricular end-diastolic volume (LVEDV), left ventricular endsystolic volume (LVESV), and left ventricular mass index (LVMI) (P < 0.01), reduced left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and decreased spherical index (SI) were (P < 0.01). The rat models also showed increased myocardial infarction area, obvious myocardial pathologies and fibrosis, increased apoptosis rate of the cardiomyocytes, enhanced myocardial expressions of p-AMPK, LC3-II/LC3-I and Beclin1 (P < 0.01), and reduced expressions of p-mTOR and p62 (P < 0.01). Fuyu Decoction treatment significantly ameliorated these changes in the rat models (all P < 0.01), but its effects were obviously blocked by treatment with EX229.
Conclusion: Fuyu Decoction can improve ventricular remodeling in rats with heart failure by inhibiting AMPK/mTOR signaling-mediated autophagy in the cardiomyocytes.
目的: 探究附萸汤对心力衰竭大鼠心室重构的影响及其与AMPK/mTOR通路介导细胞自噬的关系。
方法: 采用冠状动脉左前降支结扎法建立心力衰竭大鼠模型，将30只建模成功大鼠分成模型组（Model）、附萸汤治疗组（Fuyu Soup）、附萸汤治疗+ AMPK激动剂组（Fuyu Soup+EX229），以Wistar大鼠为假手术组（Sham），10只/组。药物干预8周后，测定心室功能及心室重构指标变化。TTC染色检测心肌梗死面积，HE和Masson观察心肌组织病理学变化，TUNEL染色检测心肌细胞凋亡，Western blot检测心肌组织p-AMPK、p-mTOR、LC3-II、Beclin1和p62蛋白表达。
结果: 与Sham组相比，Model组大鼠舒张末期左心室容积（LVEDV）、收缩末期左心室容积（LVESV）、左心室指数（LVMI）增加（P < 0.01），左心室射血分数（LVEF）、左室短轴缩短率（LVFS）、球形指数（SI）降低（P < 0.01），心肌梗死面积增加，心肌组织病理损伤及纤维化程度加重，心肌细胞凋亡率，p-AMPK、LC3-II/LC3-I、Beclin1表达升高（P < 0.01），p-mTOR、p62表达降低（P < 0.01）。与Model组相比，Fuyu Soup组大鼠LVEDV、LVESV、LVMI降低（P < 0.01），LVEF、LVFS、SI增加（P < 0.01）；心肌梗死面积降低，心肌组织病理损伤及纤维化程度减轻，心肌细胞凋亡率，p-AMPK、LC3-II/LC3-I、Beclin1表达降低（P < 0.01），p-mTOR、p62表达升高（P < 0.01）。与Fuyu Soup组相比，EX229能够逆转Fuyu Soup对心力衰竭大鼠上述指标的作用。
结论: 附萸汤具有改善心力衰竭大鼠心室重构作用，其机制与抑制AMPK/mTOR信号通路介导的心肌细胞自噬有关。
Keywords: AMPK/mTOR signaling pathway; Fuyu Decoction; autophagy; heart failure; ventricular remodeling.