PPARγ配体罗格列酮防治实验性心力衰竭大鼠左室重构改善心功能的分子机制研究  

The molecular mechanism of protective effect of PPARγ ligand rosglitazone for left ventricular remodelingand dysfunction in experimental congestive heart failure rat

作　　者：雷健[1] 刘洪智[2] 戚本玲[3] 罗兵[1] 李佐民[1] 周军[1] 贺立群[1] 曹林生[2] 

机构地区：[1]武汉市第一医院心内科,湖北省武汉市430022 [2]华中科技大学同济医学院附属协和医院心内科 [3]华中科技大学同济医学院附属协和医院老年病科

出　　处：《中国心血管病研究》2006年第6期453-456,共4页Chinese Journal of Cardiovascular Research

基　　金：武汉市科技计划项目资金资助(编号200302)

摘　　要：目的研究PPARγ配体罗格列酮对心力衰竭大鼠左室重构和心功能及心肌MMPs表达的影响,并探讨其分子机制。方法60只雄性Wistar大鼠分三组:①心力衰竭模型组(CHF,n=25),阿霉素2.5mg/kg,尾静脉注射,每周一次,连续10周;②心力衰竭模型+罗格列酮治疗组(ROS,n=25),ROS3mg/kg,每天1次,灌胃治疗;③正常对照组(CON,n=10)。12周时进行相关指标的检测。结果ROS组较CHF组死亡率降低(20%vs40%,P<0.01)。与CON组相比,CHF组大鼠左室内径扩大,心功能明显下降;ROS组左室内径增加程度降低,心功能指标改善。苦味酸天狼星红染色显示CHF组胶原容积分数(CVF)明显增高(P<0.01);而ROS组纤维化明显减轻,CVF降低(P<0.01)。CHF组左室心肌MMP-2、MMP-9及MT1-MMP表达较CON组明显升高(P<0.01),MMPs明胶酶活性显著增加(P<0.01),ROS组明显抑制MMP-2、MMP-9及MT1-MMP的表达(P<0.01),降低MMPs明胶酶活性(P<0.01),而TIMP-1的表达在三组间差异均无统计学意义(P>0.05)。NF-B活性在CHF组升高(P<0.01),而ROS干预明显降低NF-B活性(P<0.01)。结论PPARγ配体罗格列酮通过拮抗NF-B从转录水平抑制MMPs的表达及活性,进而阻止或延缓心力衰竭左室重构的进展。Objective To investigate the effect of PPARγ ligand rosglitazone on matrix metalloproteinases in left ventricular myocardium and to study the the molecular mechanism of protective effect of rosglitazone in CHF rat. Methods Sixty weightmatched adult male Wistar rats were randomly divided into 3 groups. ① the CHF group, in which 2.5 mg/kg of ADR was weekly injected via a tail vein for 10 weeks （n=25）; ② the ROS group, concomitant ADR and ROS, a PPART ligand, were administered by daily gavage at a dose of 3 mg ·kg^-1 ·day^-1 （n=25）; ③the control group （n=10）. The relevant target measurements were obtained at 12 weeks after treatment. Results Mortality was significantly lower in ROS group （20% versus 40%, P〈0.01 ）. LV cavity dilatation was significantly attenuated in ROS rosglitazone. Rosglitazone partially normalized LV contractile function, which was significantly reduced in CHF group. LV collagen volume fraction （CVF） was partly reversed by rosglitazone （P〈0.01）.The expression of LV MMP-2, MMP-9 and MT1-MMP were increased in CHF group and attenuated by rosglitazone treatment （P〈0.01）, but there was no change in TIMP-1 activity （P〉0.05）. MMP-2 and -9 gelatinolytic activity increased significantly in CHF rat （both P〈0.01 ）and attenuated by rosglitazone （both P〈0.01 ）. The DNA binding activity of NF-B increased in the CHF group （P〈0.01）,which was downregnlated by rosglitazone. Conclusion Pretreatment with PPARγ ligand rosglitasone could attenuate left ventricular remodeling by inhibiting the upregulated matrix metalloproteinases through antagonising the DNA binding activity of nuclear factor Kappa B.

关 键 词：过氧化酶体激增剂 胶原酶B NF-κB 心力衰竭 充血性 

分 类 号：Q95-33[生物学—动物学]