摘要
目的探讨血管紧张素Ⅱ(AngⅡ)受体(AT1,AT2)拮抗剂对梗死心脏心肌基质金属蛋白酶(MMP)及细胞外基质纤连蛋白(fibronectin,FN)的影响。方法结扎大鼠左冠状动脉建立心肌梗死模型,术前7天起分别用安慰剂、AT1受体拮抗剂缬沙坦(10mg.kg-1.d-1)、AT2受体拮抗剂PD123319(30mg.kg-1.d-1)。术后1、3、7天免疫沉淀法分别检测左心室游离壁(LVFW)、室间隔、右室壁心肌组织基质金属蛋白酶MMP-2、3、9及基质金属蛋白酶抑制物-1(TIMP-1)及细胞外基质FN的表达,免疫荧光检测LVFW、室间隔、右心室心肌FN的分布。结果术后7天右心室心肌排列基本正常,室间隔心肌肥厚,LVFW心肌有不同程度的坏死、肥厚及纤维化。术后1、3、7天室间隔MMP-2、3、9蛋白表达呈逐渐增加的趋势,TIMP-1及FN表达逐渐减少,各时相点与基础值相比差异有统计学意义(P<0.01);术后1、3、7天LVFWMMP-2、3、9蛋白表达一直处于高水平,TIMP-1和FN蛋白表达处于低水平,各时相点与基础值比较差异有统计学意义(P<0.01)。FN在右心室心肌组织中表达较多,其次为室间隔和LVFW,MMP-2、3、9表达与FN表达结果相反。室间隔和LVFWMMP表达,手术+缬沙坦组低于手术组和手术+PD123319组(均P<0.01),手术组与手术+PD123319组比较差异无统计学意义。手术+缬沙坦组室间隔及LVFWFN表达高于手术组和手术+PD123319组(P<0.01),手术组与手术+PD123319组比较差异无统计学意义。手术组心肌梗死面积(51.0%±2.8%)高于手术+缬沙坦组(40.4%±2.1%,P<0.05),手术组与手术+PD123319组(49.5%±2.1%)比较,差异无统计学意义。结论血管紧张素Ⅱ受体AT1拮抗剂通过增加MMP-2、3、9的表达而降解心肌细胞外基质FN参与心肌重构的病理过程,进一步恶化心功能。
Objective To investigate the effects of angiotensin Ⅱ （ Ang Ⅱ ） receptor （ AT1, AT2 ） antagonists on myocardial matrix metalloproteinases （MMPs） and fibronectin （ FN ） in rats with myocardial infarction （MI）. Methods Rat MI was induced by permanent ligation of the left coronary artery. Placebo, AT1 receptor antagonist valsartan （10 mg·kg^-1·d^-1） or AT2 receptor antagonist PD123319 （30 mg·kg^-1·d^-1） were given 7 days prior MI surgery. On the 1st, 3rd and 7th day after MI, Expressions of MMP-2,3,9, tissue inhibitors of matrix metalloproteinase-1 （TIMP-1） and FN at protein level were determined by Western blot in left ventricular free wall （ LVFW）, interventricular septum （IS） and right ventricular （RV）. Myocardial FN distribution was also assayed by immunoflorescence. Results Typical myocardial remodeling was shown in IS and LVFW 7 days after MI. MMP-2,3,9 expressions at protein level were significantly increased whereas TIMP-1 and FN expressions significantly decreased in IS 1,3,7 days post MI in a time-dependent manner compared to that of sham operated hearts. MMP-2,3,9 expressions was significantly increased and TIMP-1 and FN expression significantly decreased in LVFW at the 1st post MI day and maintained up to 7th post MI day compared to that of sham operated hearts. Up-regulated expressions of MMP-2,3,9 and down-regulated TIMP-1 and FN expressions in IS and LVFW could be significantly attenuated by valsartan but not by PD123319. Valsartan but not PD123319 also significantly reduced MI sizes（40. 4% ± 2. 1% vs 49.5% ± 2. 1%, P 〈 0. 05）. Conclusion AT1 receptor antagonist involves in the pathology procession of myocardial remodeling and might lead to the development and progression of congestive heart failure by the increasing expressions of MMP-2,3,9, which contribute to degradate extracellular matrix FN in myocardium.
出处
《中华心血管病杂志》
CAS
CSCD
北大核心
2006年第11期1029-1034,共6页
Chinese Journal of Cardiology
关键词
心肌梗塞
受体
血管紧张素
基质金属蛋白酶
纤连蛋白类
Myocardial infarction
Receptors, angiotensin
Matrix metalloproteinases
Fibronectins
