摘要
目的研究心肌细胞凋亡和心室重构在心力衰竭发展中的变化及血管内肽酶抑制剂的干预作用,探讨血管内肽酶抑制剂治疗心力衰竭的机制。方法选用雄性SD大鼠,随机分为假手术组,心肌梗死组(MI组)和心肌梗死后Omapatrilat(OMA)干预组(MI+OMA组)。经冠脉前降支结扎术建立心肌梗死模型,术后24 h MI+OMA组大鼠给予Omapatrilat 40 mg/kg.d,饮水给药,假手术组和MI组大鼠饲普通饮水。术后4、6周检测大鼠非心肌梗死区心肌细胞凋亡指数;Western蛋白印迹检测心肌细胞凋亡加速基因Bax和凋亡抑制基因Bcl-2的蛋白表达水平;VG染色测胶原容积分数(CVF);压力传感器记录左室血流动力学改变。结果(1)术后非心肌梗死区心肌细胞凋亡指数,MI组及MI+OMA组均显著高于假手术组(4周,3.8%±1.0%,2.6%±1.0%vs 0.1%±0.1%,P<0.01;6周,4.1%±1.3%,2.5%±0.9%vs 0±0,P<0.01),但MI+OMA组显著低于MI组(4周,P<0.05;6周,P<0.01);(2)与假手术组相比,MI组和MI+OMA组术后的Bax蛋白表达量均显著增高(4周,321.3%±17.5%,174.6%±13.9%vs 100.0%±8.3%,P<0.01;6周,362.3%±21.0%,193.9%±19.6%vs 104.7%±10.6%,P<0.01),但MI+OMA组显著低于MI组(P<0.01);MI组和MI+OMA组的Bcl-2蛋白表达量均低于假手术组(4周,79.3%±7.9%,86.6%±4.9%vs 100.0%±5.9%,P<0.01;6周,76.6%±9.3%,84.7%±3.4%vs 97.1%±6.0%,P<0.01),而MI+OMA组高于MI组(P<0.05);(3)MI+OMA组非梗死区CVF明显低于MI组(4周,10.5%±0.7%vs 14.7%±1.18%,P<0.01;6周,11.9%±1.4%vs 15.7%±1.1%,P<0.01),但仍显著高于假手术组(4周,10.5%±0.7%vs 3.9%±1.1%,P<0.01;6周,11.9%±1.4%vs 3.9%±1.2%,P<0.01);(4)MI组和MI+OMA组大鼠4周和6周的心功能明显降低(与假手术组比,P<0.05),而MI+OMA组大鼠的心功能显著改善(与MI组比,P<0.01)。结论血管肽酶抑制剂可通过调节凋亡相关基因Bax和Bcl-2的蛋白表达,减少心肌细胞凋亡,抑制心肌间质纤维化,从而减轻慢性心力衰竭阶段的心室重构,进而改善心功能。
Objective To investigate the effect of a vasopeptidase inhibitor on myocardial apoptosis and left ventricular remodeling in rats with heart failure. Methods Male Sprague-Dawley {SD） rats were randomly divided into three groups： sham operation, MI, and MI± omapatrilat （OMA, a vasopeptidase inhibitor）. Myocardial infarction was produced by ligation of the left anterior descending coronary artery. Twenty-four hours later, rats in the MI＋OMA group were treated with 40 mg/kg·d omapatrilat in drinking water, while rats in the sham and MI groups with placebo. Rats were sacrificed 4 or 6 weeks after operation. Myocardial apoptosis was assessed by TUNEL staining; protein expression of Bax and Bcl-2 genes was determined by Western blot ; and collagen volume fraction （ CVF ） in the noninfarcted zone by immunohistochemistry. Results （1） Cardiomyocyte apoptosis in the noninfarcted zone were significantly greater in the MI and MI4-OMA groups than in the sham group at week 4 （3.8%±1.0%, 2.6%±1.0% vs0.1±0.1%, P〈0.01） and week 6 （4.1%±1.3%, 2.5%±0.9% vs 0±0, P〈0.01）, OMA pronouncedly inhibited the enhancement （P〈0.05 at 4 week; P〈0.01 at 6 week） ; （2）Bax and Bcl-2 protein expression in the noninfarcted zone were significantly higher in the MI and MI＋OMA groups at week 4 （P 〈0.01 ） and week 6 （ P〈0.01 ） while Bax protein expression was significantly lower in MI ＋ OMA （ P〈 0.01）, and Bcl-2 protein expression was higher （P〈0.05）. （3）CVF in the MI4-OMA group was decreased than that in the Mlgroup at week 4 （10.5%±0.7% vs 14.7%±1.2%, P〈0.01） and week 6（11.9%1.4% vs 15.7%±1.1%, P〈0.01）. （4） Compared with the MI group, left ventricular function in the MI＋OMA group was significantly improved （P〈0.05）. Conclusion Vasopeptidase inhibitor prevent cardiomyocyte apoptosis, reverse left ventricular remodeling and improve cardiac function, which were associated with decreasing Bax gene expression and increasing Bcl-2 gene expression in the noninfarcted zone,
出处
《高血压杂志》
CSCD
北大核心
2006年第4期281-286,共6页
Chinese Journal of Hypertension
