氯沙坦增加Akt活性对慢性心力衰竭大鼠心功能及心肌细胞凋亡的保护作用  

Losartan attenuates cardiomyocyte apoptosis and protects cardiac function by increasing Akt activity in CHF rats

作　　者：付德明[1] 吕吉元[1] 康玉明[2] 刘卓敏[1] 

机构地区：[1]山西医科大学第一医院心血管内科,太原030001 [2]山西医科大学循环生理教研室

出　　处：《中华老年心脑血管病杂志》2009年第11期867-871,共5页Chinese Journal of Geriatric Heart,Brain and Vessel Diseases

基　　金：国家自然科学基金面上项目(30770867)

摘　　要：目的研究氯沙坦对腹主动脉结扎所致慢性心力衰竭大鼠心肌细胞凋亡和心功能保护作用的可能机制。方法采用腹主动脉缩窄法制备SD大鼠心力衰竭模型,将SD大鼠随机分为模型组,治疗组,假手术组,对照组,每组10只。治疗组和对照组氯沙坦(20 mg·kg^(-1)·d^(-1))干预8周后,采用超声心动图和心室插管法评估各组大鼠心功能,计算左、右心室质量指数(LVMI),放射免疫法检测血浆和心肌组织血管紧张素Ⅱ(AngⅡ)水平,高敏ELISA检测去甲肾上腺素(NE)水平。琼脂糖凝胶电泳和TUNEL法观察心肌细胞凋亡状态,通过RT-PCR检测凋亡相关基因表达,Western blot检测磷酸化Akt(p-Akt)蛋白水平表达变化。结果与模型组比较,治疗组大鼠心功能和LVMI等指标明显好转(P<0.05),血浆NE和心肌组织AngⅡ水平降低(P<0.05),但血浆AngⅡ水平升高(P<0.05),未出现细胞凋亡特有的"DNA梯度"现象,且凋亡指数减少(P<0.05),Bax/Bcl-2基因表达比例降低(P<0.05),p-Akt蛋白水平显著升高(P<0.05)。与假手术组和对照组相比,模型组大鼠各项心功能指标明显恶化,心肌细胞凋亡较为严重(P<0.05)。结论氯沙坦通过阻断AngⅡ与AngⅡ1型受体结合抑制凋亡通路并可促进Akt信号通路活化,从而保护慢性心力衰竭大鼠心肌细胞凋亡,改善心功能。Objective To investigate the protective effects of losartan against cardiomyocyte apoptosis in CHF rats induced by banding abdominal aorta. Methods SD rats underwent abdominal aorta coarctation to induce CHF. The rats were randomly divided into CHF model group, treatment group,sham operation group and control group, After treatment for 8 weeks with losartan in treatment and control groups or with vehicle in model and sham operation groups, heart function was assessed by ultrasound cardiography and ventricutar catheterization. Plasma and tissue Ang Ⅱ levels were measured by RIA. Cardiomyocyte apoptosis was examined by agarose gel electropho resis and TUNEL method. The mRNA levels of Bax and Bcl-2 were determined by RT-PCR and the protein expression of phosphorylated and total Akt was assessed by Western blot. Results Compared with model group, losartan-treated CHF rats had lower LVEDP （P 〈0.01）, higher LVEF （P 〈 0.05）, and lower myocardium Ang Ⅱ , but higher plasma/Ang Ⅱ （P〈 0.05）, and had no obvious ＂DNA ladder＂ which was characteristic of apoptosis. The apoptosis index was also reduced with lower expression of Bax/Bcl-2 gene and a higher protein expression of p-Akt （P〈0.05）. Conclusion Losartan might inhibit cardiomyocyte apoptosis and improve cardiac function in CHF rats by blocking Ang Ⅱ to bind to AT1-R and promoting the activation of Akt.

关 键 词：心力衰竭 肌细胞 心脏 细胞凋亡 超声心动描记术 抗高血压药 

分 类 号：R541.6[医药卫生—心血管疾病]