吴强,杨永曜,李隆贵,杨天和,蔡运昌,蒋清安
WU Qiang1,YANG Yongyao1,LI Longgui2,YANG Tianhe1,CAI Yunchang1,JIANG Qing'an1(1.Department of Cardiology

• 1:贵州省人民医院心内科
• 2:贵州省人民医院心内科
• 3:第三军医大学新桥医院心内科
• 4:贵州省人民医院心内科

摘要(Abstract)：

目的:探讨过氧化物酶体增殖物激活型受体α和γ(PPARα和PPARγ)配体非诺贝特、吡格列酮对大鼠压力超负荷左心室肥厚过程中心肌细胞凋亡的调控作用,并观察其对凋亡相关基因Fas/FasL表达变化的影响。方法:雄性Wistar大鼠腹主动脉缩窄复制压力超负荷模型,术后48h存活的40只随机分成手术组(CAA组)、非诺贝特组[F组,30mg/(kg.d)]、吡格列酮组[P组,3mg/(kg.d)]及非诺贝特和吡格列酮合用组[F+P组,非诺贝特30mg/(kg.d),吡格列酮3mg/(kg.d)]。以假手术组(SH组)为对照,在给药处理8周后观察心肌超微结构、血流动力学参数、心室重塑指标、心肌细胞凋亡指数(CAI)及凋亡相关基因Fas/FasL蛋白表达的变化。结果:压力超负荷大鼠心肌细胞出现凋亡的特征超微结构变化;F组、P组及F+P组的左室湿重/体重、平均动脉压、左室收缩压、左室舒张末期压、心率、CAI及Fas/FasL蛋白的表达低于CAA组,而左室压力上升、下降最大速率高于CAA组;上述指标在F组、P组及F+P组间差异无统计学意义。结论:PPARα和γ信号通路激活能抑制压力超负荷大鼠的心肌肥厚和心肌细胞凋亡,改善血流动力学;PPARα、PPARγ配体合用无叠加效应。
Objective:To investigate the effects of ligands of peroxisome proliferator-activated receptors(PPARs),fenofibrate,and pioglitazone,on cardiocyte apoptosis and the expression of apoptosis-associated gene,Fas and Fas ligand(FasL),in pressure-overload rats.Methods:A pressure overloading model was established by the constriction of abdominal aorta in Wistar rats.In forty-eight hours after that,40 survived rats were randomly divided into four groups:coarctation of abdominal aorta group(group CAA),fenofibrate group(group F,30mg·kg-1·d-1),pioglitazone group(group P,3mg·kg-1·d-1),and concomitant fenofibrate and enalapril group(group F+P,30mg·kg-1·d-1 and 3mg·kg-1·d-1).Ten sham-operated rats were served as non-pressure overload control group(group SH).Fenofibrate and pioglitazone were delivered by direct gastric gavage.After 8 weeks of medical therapy,hemodynamic studies were performed on rats in each group,and the ratio of left ventricular weight to body weight(LVW/BW)and the ratio of right ventricular weight to body weight(RVW/BW)were measured.The morphological features of apoptotic myocardiac cells were observed with transmission electron microscopy.DNA fragmentations were determined semiquantitatively by in situ TDT-mediated dUTP nick end labeling(TUNEL).Using Western blot,the apoptosis-associated gene Fas and FasL expression was observed.Complete experimental data obtained in 44 rats were analyzed statistically.Results:The characteristic features of apoptotic myocardial cells were recognized by transmission electron microscopy in all groups except group SH.Left ventricular hypertrophy and hemodynamic parameters were ameliorated,and the cardiocyte apoptosis was significantly reduced by fenofibrate and pioglitazone(P<0.05).Compared with group SH,the Fas/FasL expression increased at protein levels in groups CAA,F,P and F+P(P<0.05).The protein levels of Fas/FasL in all rats of three drug treated groups were lower than that in group CAA(P<0.05).There was no significant difference of the above mentioned indices among the three treatment groups(P>0.05).Conclusions:Treatment of agonist of PPARα and PPARγ may be useful in improving of hemodynamic indexes,preventing of cardiac hypertrophy and apoptosis which is related to downregulation of Fas and FasL expression.There is no additive effect when combination of the two drugs is used.

关键词(KeyWords)： 细胞凋亡;心肌;肥大,左心室;大鼠;过氧化物酶体增殖物活化型受体;非诺贝特;吡格列酮
apoptosis;myocardium;hypertrophy,left ventricular;peroxisome proliferator-activated receptors;fenofibrate;pioglitazone;rats

Abstract:

Keywords:

基金项目(Foundation): 贵州省优秀科技教育人才省长专项资金资助项目[黔科教办(2003)04];; 贵州省科技攻关项目[黔科合(2004)NGY043]

作者(Author): 吴强,杨永曜,李隆贵,杨天和,蔡运昌,蒋清安
WU Qiang1,YANG Yongyao1,LI Longgui2,YANG Tianhe1,CAI Yunchang1,JIANG Qing'an1(1.Department of Cardiology

DOI: 10.19367/j.cnki.1000-2707.2007.06.003

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