培哚普利对心肌梗死大鼠内质网应激分子GRP78和Caspase-12表达的影响

Effect of perindopril on endoplasmic reticulum stress-related protein GRP78 and caspase-12 in rats with myocardial infarction

目的探讨培哚普利改善心功能的作用与内质网应激反应(ERS)的关系。方法通过结扎大鼠冠状动脉前降支建立心肌梗死模型,将24h内存活大鼠随机分为模型组(n=8)和培哚普利组(n=8),另设假手术组作为对照(n=8)。术后第2天起培哚普利组以2mg/(kg.d)培哚普利灌胃给药,模型组和假手术组按体重给予等量生理盐水,每天1次,持续4周。采用超声心动图检测左室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD)、射血分数(LVEF)以及短轴缩短率(FS)等指标。免疫组织化学或Western blotting检测内质网应激相关蛋白GRP78和Caspase-12的表达水平。结果与假手术组相比,心肌梗死4周后,模型组LVEDD和LVESD明显升高,LVEF和FS明显下降,内质网应激相关蛋白GRP78和Caspase-12表达增加,培哚普利明显缓解了上述指标的变化。结论培哚普利改善心功能的作用可能是通过降低GRP78和Caspase-12的表达,阻断ERS途径实现的。

Objective To investigate whether the effect of perindopril on ameliorating heart function is associated with inhibiting endoplasmic reticulum stress （ERS） signaling pathway. Methods Myocardial infarction （MI） models in male SD rats were reproduced by ligation of the left anterior descending coronary artery （LAD）. Rats that survived post-MI within 24h were randomly divided into model group （n=8） and perindopril group （n=8）. Eight sham-operated rats were used as controls which underwent the same surgical procedure except that the suture around the coronary artery was not tied. The rats in peridopril group were treated with peridopril in a dose of 2mg/（kg.d） for 4 weeks. The rats in model group and sham group received an equal amount of saline. At the end of 4 weeks, transthoracic echocardiogram was performed to measure the ventricular morphology and heart function, including left ventricular end systolic diameter （LVESD） and end diastolic diameter （LVEDD）, as well as left ventricular ejection fraction （LVEF） and fraction shortening （FS）. The expression levels of GRP78 and caspase-12 protein were assessed with immunohistochemistry or Western blotting. Results Compared with the sham-operated group, the LVEDD and LVESD significantly increased after 4 weeks of MI, while the EF and FS decreased in model group. Perindopril significantly inhibited ventricular hypertrophy and improved heart function （P〈0.05）. Western blotting or immunohistochemistry showed that the important endoplasmic reticulum stress markers, GRP78 and caspase-12 significantly increased in perindopril treated rats after MI, showing that perindopril significantly attenuated these changes. Conclusion Perindopril may improve the heart function, which may be partly related to a decrease in the expression level of GRP78 and caspase- 12, and by blocking ERS signaling pathway.