卡托普利对大鼠急性心肌梗死后非梗死区胶原重塑及MMP-8/TIMP-2表达的影响

Effects of Captopril on Collagen Remodeling and Expression of MMP-8/TIMP-2 on Non-infarction Zone after Acute Myocardial Infarction in Rats

目的探讨大鼠急性心肌梗死后心肌间质内基质金属蛋白酶(MMP-8),组织金属蛋白酶抑制物(TIMP-2)对心肌Ⅰ、Ⅲ型胶原表达的影响及与心室重塑的关系,以及血管紧张肽转换酶抑制药卡托普利的干预作用。方法将雄性Wistar大鼠结扎左冠状动脉前降支建立急性心肌梗死模型,随机分为梗死对照组12只和卡托普利治疗组10只。另设假手术组10只。卡托普利治疗组于术后24h给予卡托普利10mg.kg-1.d-1灌胃,其他两组给予等体积0.9%氯化钠注射液灌胃,测定各组4周末心室重塑和血液动力学指标,免疫组化检测左室非梗死区MMP-8,TIMP-2蛋白表达,天狼猩红染色偏振光显微镜下测量左室非梗死区Ⅰ、Ⅲ型胶原容积分数。结果与假手术组比较,梗死对照组大鼠4周末心肌组织MMP-8、TIMP-2表达均明显增高(均P<0.01),但TIMP-2增高幅度明显低于MMP-8,MMP-8/TIMP-2比值显著增高(P<0.01),非梗死区Ⅰ、Ⅲ型胶原均明显升高(均P<0.01),Ⅰ/Ⅲ比值未见明显差异。另外梗死对照组的左室舒张末压(LVEDP)、相对左心室质量(LVRW)、相对右心室质量(RVRW)均显著增加(均P<0.01),左室内压最大上升和下降速率(±dp/dt)均显著降低(均P<0.01)。与梗死对照组相比,卡托普利治疗组MMP-8,Ⅰ、Ⅲ型胶原和MMP-8/TIMP-2比值均显著降低(均P<0.01),而TIMP-2无明显变化。并且LVEDP、LVRW、RVRW均显著减轻(均P<0.01),左室内压±dp/dt均显著升高(均P<0.01)。结论卡托普利对急性心肌梗死(AMI)后大鼠非梗死区Ⅰ、Ⅲ型胶原含量的增生有抑制作用,并能抑制AMI后大鼠非梗死区MMP-8蛋白表达量和下调MMP-8/TIMP-2比值。

Objective To study the effect of MMP-8,TIMP-2 on protein expression of Ⅰ,Ⅲ collagen after myocardial infarction in rats and the intervention effects of captopril. Methods Rats survived from AMI induced by left anterior descending branch ligation were randomized to AMI control group（ 12 cases） and captopril treatment group（ 10 cases, i. g. 10 mg · kg^-1·d^-1 24 h after operation）. At the end of the forth week, the ventricular remodeling index, expression of myocardium MMP-8, TIMP-2 protein in left ventricular noninfarcted myocardium were examined by immunohistochemical analysis ; type Ⅰ and type Ⅲ collagen volume fraction （CVF） were analyzed by using polarized light with picrosirius red satining. Results Compared with sham-operated rats, the protein expression of MMP-8, TIMP-2 and MMP-8/TIMP-2 ratio in AMI control group were significantly increased （P 〈 0.01 ）, but increasing extent of TIMP-2 was less than that of MMP-8. Type Ⅰ and Ⅲ collagen in the noninfarcted myocardium were increased subsequently （allP 〈 0. 01 ）, while left ventricular （LV） end diastolicpressure（ LVEDP）, relative weight（ LVRW）, right ventricular relative weight （RVRW） were significantly increased（ all P 〈 0.01 ） ; whereas ＋ dp/dt were significantly reduced （ P 〈 0.01 ） at 4 weeks after AMI. In comparison with the AMI control group, the protein expression of MMP-8 , the CVF of type Ⅰ , Ⅲ collagen and MMP-8/TIMP-2 ratio were in captopril treatment group were significantly reduced （ all P 〈 0.01 ）, while there were no significantly changes in the expression of TIMP-2. And LVEDP, LVRW, RVRW were lower as well （ all P 〈 0.01 ）. Whereas ＋ dp/d was significantly increased （ P 〈 0.01 ） . Conclusion Captopril could not only inhibit the growth of type Ⅰ , Ⅲ collagen in AMI and NIZ, but also reduce the MMP-8 expression and down-regulate the ratio of MMP-8/TIMP after AMI.