辛伐他汀抑制心肌细胞Rho A、Rho GTPase表达对心室肥厚的影响

Effect of simvastatin on cardiac hypertrophy in rabbits with chronic heart failure

目的探讨辛伐他汀对心力衰竭模型兔抑制心肌肥厚、改善心功能的影响及机制。方法24只新西兰白兔,均分四组,除假手术组外,通过破坏主动脉瓣和缩窄腹主动脉,增加左心室前、后负荷,建立慢性心力衰竭模型;术后(除心衰对照组)早干预组(即起,连续8周)和晚干预组(第5周起,连续4周)予辛伐他汀每天5mg/kg灌胃,实验结束取心肌细胞,Western-blot检测细胞膜RhoA蛋白表达,[γ-32P]电泳分析RhoGTPase活性;实验前、结束时均行超声心动图检查。结果心衰对照组室间隔厚度(LVSd)、左心室舒张期内径(LVIDd)、左心室后壁厚度(LVPwd)、左心室收缩期内径(LVIDs)、心脏重量(HW)、左心室重量(LVW)、心脏/体重(HW/BWradio)、左心室/体重(LVW/BWradio)明显高于假手术和早、晚干预组(P<0.05,P<0.01);左室射血分数(EF)、左室长轴缩短率(FS)明显低于假手术组和早、晚干预组(P<0.05,P<0.01);心肌细胞膜RhoA蛋白表达、RhoGTPase活性明显高于假手术组和早、晚干预组(P<0.01)。结论辛伐他汀可抑制细胞膜RhoA蛋白表达、RhoGTPase活性,从而抑制心肌肥厚、改善心功能。

Objective To study the effects of simvastatin on cardiac hypertrophy and cardiac function in rabbits with chronic congenital heart failure（CHF）.Methods Twenty-four New Zealand rabbits were divided into 4 groups of A,B,C and D with 6 rabbits each.Group D underwent sham operation as healthy control.After establishment of CHF,the rabbits in group A were given oral simvastatin 5 mg·kg-1·d-1 after the operation for 8 weeks,those in group B were given oral simvastatin 5 mg·kg-1·d-1 for 4 weeks started at 4 weeks after the operation,and those in group C were not given simvastatin as the controls.At the end of 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.Rho A expression in cardiomyocyte membrane was detected with Western blot.Rho GTPases activity was determined by [γ-32P] GTP-binding assay.Results Compared to groups of A and B,the HW,LVW,HW/BW radio,and LVW/BW radio were significantly higher and the IVSD,LVIDs,LVPWd and LVIDd were significantly increased in group C（P0.01,P0.05）.The EF and FS were significantly lower in CHF groups than those in group D（P0.01,P0.05）.The expression of Rho A in cell membrane and the activity of Rho GTPase were significantly higher in group C than those in the other 3 groups（P0.01）.Conclusion Simvastatin can inhibit cardiac hypertrophy and improve cardiac function by depressing the expression of Rho A in heart cell membrane and decreasing the activity of Rho GTPase in rabbits model with CHF.