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瑞舒伐他汀通过AMPK信号通路调节自噬保护急性心肌梗死大鼠

[Rosuvastatin protects acute myocardial infarction rats through autophagy regulation via AMPK signaling].

作者信息

Song Z C, Chen L, Zhang D, Zhang S Y, Lin X

机构信息

Department of Cardiology, Fushun Central Hospital, Fushun 113006, China.

出版信息

Zhonghua Yi Xue Za Zhi. 2018 Nov 20;98(43):3536-3541. doi: 10.3760/cma.j.issn.0376-2491.2018.43.015.

Abstract

To investigate the effects of rosuvastatin (RSV)on autophagy and apoptosis of myocardial cells in rats with acute myocardial infarction. SD rats were divided into control (Sham group), acute myocardial infarction model rats (AMI group), AMI rats treated by RSV with the dose of 5 mg·kg(-1)·d(-1) (RSV group), AMI rats treated by RSV and AMPK inhibitor Compound C at the same time (RSV+ CC group)(=8) based on simple random sampling methods.Rat myocardial cell line H9c2 was divided into control group, Hypoxia group, Hypoxia+ RSV group, Hypoxia+ RSV+ Compound C group, Hypoxia+ AICAR (AMPK activator)group.After 6 weeks, the rats were examined by hemodynamics, and pathological observation of myocardial tissue by HE staining was also carried out.RT-PCR/Western blot were used to detect the expression of Beclin1, p62, BAX and Bcl-2 mRNA or protein of different groups and .Western blot was used to detect the expression of mTOR and AMPK protein and phosphorylation in cardiac tissue of each group. In this study, the rat model of acute myocardial infarction was successfully prepared.Compared with the AMI group, the myocardium inflammation in the RSV group was alleviated, the LVMI decreased significantly, LVSP increased significantly, LVEDP decreased significantly, HR decreased significantly, the absolute value of dP/dTmax and -dP/dTmax increased significantly.The levels of Beclin1 and Bcl-2 mRNA were significantly up-regulated from 0.43 to 2.01 and 0.30 to 0.72, the expression of p62 and BAX mRNA decreased in half, the phosphorylation level of AMPK was significantly up-regulated, and the level of mTOR phosphorylation significantly reduced(<0.05). These changes were antagonized by AMPK inhibitors in RSV+ CC group. experiments showed that, after RSV intervening, the levels of Beclin1 and Bcl-2 mRNA and protein in the myocardial cells of Hypoxia group significantly increased in triple, while the expressions of p62 and BAX mRNA and protein significantly decreased above a half.The above changes were consistent with those of the AMPK activator group and were antagonized by Compound C. RSV can effectively promote autophagy and decrease apoptosis in rat heart after myocardial infarction through AMPK/mTOR pathway.

摘要

探讨瑞舒伐他汀(RSV)对急性心肌梗死大鼠心肌细胞自噬和凋亡的影响。采用简单随机抽样方法将SD大鼠分为对照组(假手术组)、急性心肌梗死模型大鼠组(AMI组)、5 mg·kg⁻¹·d⁻¹剂量RSV治疗的AMI大鼠组(RSV组)、同时给予RSV和AMPK抑制剂Compound C的AMI大鼠组(RSV + CC组)(每组n = 8)。将大鼠心肌细胞系H9c2分为对照组、缺氧组、缺氧 + RSV组、缺氧 + RSV + Compound C组、缺氧 + AICAR(AMPK激活剂)组。6周后,对大鼠进行血流动力学检测,并采用HE染色对心肌组织进行病理观察。采用RT-PCR/蛋白质印迹法检测不同组Beclin1、p62、BAX和Bcl-2 mRNA或蛋白的表达,并采用蛋白质印迹法检测各组心脏组织中mTOR和AMPK蛋白表达及磷酸化水平。本研究成功制备了大鼠急性心肌梗死模型。与AMI组相比,RSV组心肌炎症减轻,左心室质量指数(LVMI)显著降低,左心室收缩压(LVSP)显著升高,左心室舒张末压(LVEDP)显著降低,心率(HR)显著降低,dP/dTmax和 -dP/dTmax绝对值显著升高。Beclin1和Bcl-2 mRNA水平从0.43显著上调至2.01、从0.30上调至0.72,p62和BAX mRNA表达降低一半,AMPK磷酸化水平显著上调,mTOR磷酸化水平显著降低(P < 0.05)。RSV + CC组中这些变化被AMPK抑制剂拮抗。细胞实验表明,RSV干预后,缺氧组心肌细胞中Beclin1和Bcl-2 mRNA及蛋白水平显著增加至三倍,而p62和BAX mRNA及蛋白表达显著降低超过一半。上述变化与AMPK激活剂组一致,并被Compound C拮抗。RSV可通过AMPK/mTOR通路有效促进大鼠心肌梗死后心脏的自噬并减少凋亡。

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