辛伐他汀对慢性心力衰竭兔心肌PPARγ mRNA、蛋白表达及核因子κB表达、活性的影响

Simvastatin prevents hypertrophy and keeps cardiac function in myocardium of rabbit with overlord by promoting PPAR gamma and inhibiting NF-kappa B

目的观察辛伐他汀对兔慢性心力衰竭模型心肌肥厚、心功能的影响,探讨辛伐他汀抑制心肌肥厚、改善心功能的机制。方法24只新西兰白兔分为4组,1组为假手术组。2、3、4组给予主动脉瓣返流及腹主动脉缩窄术,其中2组为心衰对照组;3组:早干预组,术后给予辛伐他汀5mg·kg-1·d-1灌胃连续8wk;4组:晚干预组,术后4wk给予辛伐他汀5mg·kg-1·d-1灌胃连续4wk。观察开始及结束时左室舒张末压(LVEDP)。实验结束时,观察左心室重量(LVW)、心脏重量(HW),计算左心室重量指数(LVW/BW)、心脏重量指数(HW/BW)。RT-PCR分析各组PPARγmRNA表达。Western blot分析心肌细胞核PPARγ和p65蛋白表达,电泳迁移率变动试验分析p65活性。结果早、晚干预组LVW、HW、HW/BW均低于心衰对照组(P<0.05,P<0.01),早干预组(LVW/BW)低于心衰对照组(P<0.01)。早、晚干预组左室舒张末压低于心力衰竭组(P<0.01)。心衰对照组心肌组织PPARγ蛋白和mRNA表达低于假手术组(P<0.01),p65蛋白表达及活性高于假手术组(P<0.01)。辛伐他汀干预后,早干预组、晚干预组PPARγ蛋白和mRNA表达增加(P<0.01),p65蛋白表达及活性降低(P<0.01)。结论辛伐他汀抑制心肌肥厚、改善心功能,其机制与增加PPARγ表达、降低p65蛋白表达及活性有关。

Aim To observe the effects of simvastatin on PPARγ and p65 subunit of NF-κB and to invest the mechanism of simvastatin preventing hypertrophy and keeping cardiac function. Methods 24 rabbits were divided into 4 groups. Rabbits received sham operation as health control in group I. In other groups,aortic regurgitation and coarctation of ascending aorta were operated in rabbits. Rabbits received no drugs in Group Ⅱ. In group Ⅲ,rabbits were given simvastatin 5 mg ·kg-1·d-1 after the operation for 8 weeks. In group Ⅳ,rabbits were given simvastatin 5 mg·kg-1·d-1 after 4 weeks of operation for 4 weeks. At the beginning and the end of the experiment,left ventricular end diastolic pressure （LVEDP） was measured with catheter. At the end of the experiment, heart weight （HW）,left ventricular weight （LVW）,body weight （BW）,heart weight/body weight radio （HW/BW radio）, left ventricular weight/body weight radio （LVW/BW radio） were measured. The PPARγ mRNA expression was analyzed by RT-PCR. PPARγ and p65 protein expression in cardiomyocyte nuclear were analyzed through Western blot. The activity of p65 was analyzed with EMSA. Results The HW,LVW,HW/BW were significantly decreased in the early and late treatment group than in CHF group （P〈0.05,P〈0.01）. The LVW/BW was significantly decreased in early treatment group than in CHF group,too （P〈0.01）. The LVEDP was significantly decreased in the early and late treatment group than in CHF group （P〈0.01）. The mRNA and protein of PPARγ significantly fell in CHF heart （P〈0.01）. The activity and protein expression of p65 were significantly increased in CHF heart （P〈0. 01）. Simvastatin increased the mRNA and protein expression of PPARγ and decreased the ac-tivity and protein expression of p65 （P〈0.01）. Conclusions Simvastatin inhibits the cardiac hypertrophy and improves cardiac function. The mechanism of simvastatin on cardiac remodeling and function relates to the increase of PPARγ expression and preventing the NF-κB activation.