洛沙坦对大鼠心肌梗死后心肌间质基质金属蛋白酶2和金属蛋白酶组织抑制因子2表达的干预作用

Interventional effect of losartan on expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in myocardial extracellular matrix in rats after myocardial infarction

目的:观察大鼠心肌梗死后心肌间质基质金属蛋白酶2及金属蛋白酶组织抑制因子2的表达和心室重塑、心功能变化的关系及洛沙坦干预的影响。方法:实验于2004-09/2005-08在华中科技大学协和医院心血管研究所实验室进行。①取180只SD大鼠,随机取8只为假手术组(不结扎冠状动脉),其余172只大鼠结扎冠状动脉前降支复制急性心肌梗死模型。②将造模成功的67只大鼠随机分成洛沙坦组[灌胃洛沙坦30mg/(kg·d),1次/d]和模型组(灌胃等量生理盐水),两组分为术后1,7,14,28d4个亚组。③应用反转录-聚合酶链反应法及免疫组化方法检测基质金属蛋白酶2,金属蛋白酶组织抑制因子2及Ⅰ/Ⅲ胶原的表达,超声心动图评价大鼠心功能变化和心室重塑的过程。结果:75只大鼠进入结果分析。①基质金属蛋白酶2及金属蛋白酶组织抑制因子2蛋白表达:模型组除术后1d基质金属蛋白酶2表达与假手术组无差异外,其他各时间点表达均高于假手术组(P<0.05);洛沙坦组术后7,14,28d金属蛋白酶2表达均低于模型组(P<0.05)。②基质金属蛋白酶2及金属蛋白酶组织抑制因子2mRNA表达:模型组各时间点均高于假手术组(P<0.05),洛沙坦组术后1,14,28d基质金属蛋白酶2mRNA表达均低于模型组(P<0.05)。③心肌Ⅰ/Ⅲ胶原比例:术后14,28d,模型组显著高于假手术组(P<0.05),洛沙坦组低于模型组(P<0.05)。④超声心动图显示模型组大鼠在术后7,14,28d时心功能明显低于假手术组(P<0.01),洛沙坦组14,28d时心功能指标均较模型组明显改善(P<0.05)。结论:大鼠心肌梗死后心肌间质金属蛋白酶2、金属蛋白酶组织抑制因子2表达增高,非梗死区Ⅰ/Ⅲ胶原比例升高可能是心室重塑和心力衰竭发生发展的原因之一。洛沙坦可通过抑制金属蛋白酶2表达,逆转Ⅰ/Ⅲ胶原比例改善心肌梗死后心室重塑及心力衰竭。

AIM： To observe the relationship between expression of matrix metalloproteinase-2 （MMP-2） and tissue inhibitor of metalloproteinase-2 （TIMP-2） of myocardial extraeellular matrix after myocardial infarction in rats and changes of cardiac function and ventricular remodeling as well as the interventional effect of losartan. METHODS： The experiment was conducted in the Laboratory of Cardiovascular Institute, Union Hospital, Huazhong University of Science and Technology. ①180 SD rats were selected, of which 8 rats were randomly selected as sham-operation group （without coronary artery ligation）, the rest 172 ones were made into models of acute myocardial infarction （AMI） after coronary artery ligation.②Sixty-seven rats with successful modeling were randomly divided into losartan group （administrated with gastric perfusion of losartan 30 mg/kg once per day） and model group （administrated with gastric perfusion of normal saline of the same volume）, then both groups were subdivided into 1, 7, 14, 28 days postoperation groups.③Expressions of MMP-2, T1MP-2 and Ⅰ/Ⅲ collagen were assessed with reverse transcription polymerase chain reaction （RT- PCR） method and immunohistochemistry. Changes of cardiac function and cardiac remodeling in rats were evaluated with echocardiogram. RESULTS： A total of 75 rats were involved in the analysis of results.① Expressions of MMP-2 and TIMP-2： Except the expression of MMP-2 one day after opertaion, those in other time-points in the model group were higher than those in the sham-opertaion group （P 〈 0.05）; Expressions of MMP-2 7, 14, 28 days after operation in the losartan group were lower than those in the model group （P 〈 0.05）. ②Expressions of MMP-2 and T1MP-2 mRNA： Those in each time-point in the model group were higher than those in the sham-operation group （P 〈 0.05）. ③Myocardial Ⅰ/Ⅲ collagen ratio： 14, 28 days after operation, it was significantly higher in the model group than that in the sham-operation group and losartan group （P 〈 0.05）. ④Echocardiogram indicated that 7, 14, 28 days after operation, the cardiac function of rats in the model group was significantly lower than that in the sham-operation group （P 〈 0.05）, and amelioration of cardiac function indexs at the 14^th day and 28^th day after operation in the sham-operation group were obviously better than that in the model group. CONCLUSION： Expressions of MMP-2 and TIMP-2 of myocardial extraeellular matrix in rats with myocardial infarction have increased, and the increasing of Ⅰ/Ⅲ collagen ratio in the non-infarction area may be one of the reasons why ventficular remodeling and heart failure occurres and develops. Losartan can ameliorate ventricular remodeling and heart failure after myocardial infarction by inhibiting the expression of MMP-2 and reversing the ratio of Ⅰ/Ⅲ collagen.