米诺环素对急性心肌梗死大鼠心肌基质金属蛋白酶-2及转化生长因子-β_1表达的影响

Effect of minocycline on expression of matrix metalloproteinase-2 and transforming growth factor-beta1 of myocardial extracellular matrix after infarction in the rats

目的:探讨大鼠心肌梗死后心肌间质基质金属蛋白酶-2(MMP-2)及转化生长因子-β1(TGF-β1)的表达与心室重塑的关系及米诺环素的干预影响。方法:结扎SD大鼠冠状动脉前降支建立急性心肌梗死模型,随机分成心肌梗死对照组和米诺环素(30mg·kg-1.d-1)治疗组,2组又随机分为1、2和4周亚组;另设假手术组。应用免疫组化方法测定胶原的表达。用逆转录-聚合酶链反应法及免疫组化方法检测MMP-2、TGF-β1mRNA和蛋白表达情况。结果:与假手术组相比,心肌梗死对照组MMP-2、TGF-β1的mRNA表达在各亚组明显升高(均P<0.05),各亚组MMP-2、TGF-β1蛋白表达也均增高(均P<0.05),非梗死区Ⅰ/Ⅲ胶原比例在2周和4周随之升高(均P<0.05)。而米诺环素治疗组MMP-2mRNA和蛋白表达在1、2和4周亚组,TGF-β1mRNA和蛋白表达在1、2周亚组,均较心肌梗死对照组显著降低(均P<0.05),Ⅰ/Ⅲ胶原比例在2周和4周亚组也显著降低(均P<0.05)。结论:大鼠心肌梗死后心肌间质内MMP-2、TGF-β1的表达增高,非梗死区Ⅰ/Ⅲ胶原比例上升,是心室重塑发生发展的重要机制。米诺环素可通过抑制MMP-2、TGF-β1的表达,逆转Ⅰ/Ⅲ胶原比例改善心肌梗死后心室重塑。

Objective：To investigate the relationship of expression of matrix metalloproteinase-2 （MMP-2）and transforming growth factor-betal （TGF-β1） on ventricular remodeling following myocardial infarction in the rats and the effects of minocycline. Method： Adult male Sprague -Dawley rats underwent the left descending coronary artery ligation,were divided randomly into AMI control group and AMI minocycline treatment group （30 mg·kg^-1·d^-1） . Rats in these two groups were redivided into 3 subgroups according to the course of treatment： 1 week, 2 week, 4 week subgroups. Eight rats underwent sham operation, were killed at 4 w after operation. The protein expression of Ⅰ, Ⅲ collagen was assessed by the method of immunohistochemical stain, mRNA and protein expression of MMP-2 and TGF-β1 was examined by reverse transcription- polymerase chain reaction （RT- PCR） and immunohistochemistry. Result：Compared with sham rats, the mRNA expression of MMP-2 and TGF-β1 significantly increasd in all three subgroups of AMI controls（all P〈0.05）, and the protein expression of MMP-2 and TGF-β1 were enhanced in all subgroups （all P〈0.05）. Ⅰ/Ⅲ collagen ratio in the noninfarcted myocardium increased subsequently at 2 nd, 4 th week （all P〈0.05）. In comparison with the AMI control group, the mRNA expression and the protein expression of MMP-2 were significantly lower in the 1 w, 2 w and 4 w sub-groups of minocycline group（all P〈0.05） and so were the expression of TGF-β1 in the 1 w, 2 w sub-groups（all P〈0.05）. Ⅰ/Ⅲ collagen ratio were also significantly decreased in the 2 w, 4 w sub-groups of the minocycline group （all P〈0.05）. Conclusion： MMP-2 and TGF-β1 play important roles in postinfarction extracellular matrix remodeling. Minocycline can prevent ventricular remodeling by suppressing the expression of MMP-2, TGF-β1 and reversing the ratio of Ⅰ/Ⅲ collagen.