强力霉素对大鼠急性心肌梗死后心肌基质金属蛋白酶及其组织型抑制剂表达的影响  

Effects of doxycycline on the expression of matrix metalloproteinase and tissue inhibitor of MMP in myocardium after acute myocardial infarction; an animal experiment with rats

作　　者：张沛[1] 杨跃进[1] 陈曦[2] 阮英茆[3] 周燕文[4] 田毅[4] 陈在嘉[1] 

机构地区：[1]中国医学科学院中国协和医科大学心血管研究所阜外心血管病医院冠心病研究室,北京100037 [2]中国医学科学院中国协和医科大学心血管研究所阜外心血管病医院生化研究室,北京100037 [3]中国医学科学院中国协和医科大学心血管研究所阜外心血管病医院病理科,北京100037 [4]中国医学科学院中国协和医科大学心血管研究所阜外心血管病医院实验外科,北京100037

出　　处：《中华医学杂志》2004年第15期1288-1293,共6页National Medical Journal of China

基　　金：国家"八六三"计划分题资助项目(102-08-02-05)

摘　　要：目的 评价基质金属蛋白酶(MMP)抑制剂强力霉素(Dox)对急性心肌梗死(AMI)大鼠左室非MI区心肌MMP-8和13、MMP组织型抑制剂(TIMP)-1和2的表达及胶原重构的影响。方法 将雌性SD大鼠于AMI术后24 h随机分为:AMI对照组和Dox(30 mg·kg-1·d-1)治疗组,并开始给药治疗。另设假手术组。上述各组再均随机分为1周、2周和4周3个疗程亚组。满疗程后处死大鼠,测定左室MI面积;以RT-PCR和Western印迹法测定非MI区两种MMP和TIMP的mRNA和蛋白表达;免疫组化染色测定非MI区Ⅰ/Ⅲ型胶原含量(CVF)。结果 MI面积在AMI对照和治疗组各时间点亚组间差异均无显著意义(42％-48％,均P>0.05)。与假手术组相比,AMI对照组的MMP-8和13蛋白表达在各时间亚组均显著增高(均P<0.05),mRNA表达则在1周和4周亚组均显著增高(均P<0.05);而TIMP-1 mRNA和蛋白表达仅在1周亚组时均显著增高(均P<0.05);TIMP-2 mRNA表达在各时间点亚组均显著增高(均P<0.05),而蛋白表达仅在2和4周亚组时均显著增高(均P<0.05);最后非MI区Ⅰ/Ⅲ型CVF在各时间亚组均显著升高(P<0.05-0.001)。与AMI对照组相比,Dox对大鼠AMI后MMP-8、13和TIMP-1、2 mRNA和蛋白表达的增强均有显著抑制作用(均P<0.05);使Ⅰ型CVF减少(P<0.01-0.001),但对Ⅲ型CVF于各时间点亚组均无显著影响。结论Objective To assess the effects of doxycycline, a matrix metalloproteinase (MMP) inhibitor, on the expression of MMP-8 and -13, and tissue inhibitor of MMP-1 and -2 (TIMP-1 and -2) , and on collagen remodeling in the noninfarcted myocardium after acute myocardial infarction ( AMI) . Methods 212 female SD rats underwent ligation of left coronary artery so as to cause AMI. Twenty-four hours after the 127 surviving rats were randomly divided into 2 groups; AMI control group (n =64) and AMI doxycycline treatment (30 mg · kg-1 · d-1) group ( n =63). Then the rats in these 2 groups were re-divided into 3 sub-groups of 18 -24 rats according to the course of treatment: 1-week, 2-week, and 4-week subgroups. Thirty female SD rats underwent sham operation and then were re-divided into 3 groups of 10 rats: 1 -week, 2 -week, and 4-week subgroups. By the end of each course the rats were killed and their hearts were taken out. A piece of myocardium from the left ventricle was taken and stained with hematoxyline and eosin to examine the area of infarction. The mRNA expressions of MMP and TIMP in the non-infarcted myocardium were detected by RT-PCR. The protein expressions of MMP and TIMP in the non-infarcted myocardium were detected by Western blotting. The type Ⅰ and type Ⅲ collagen volulme fraction (CVF) in the noninfarcted myocardium was examined by immunohistochemistry. Results There was no significant difference in the MI size among the 6 subgroups of AMI control and doxycycline groups (42% -48% ,all P > 0. 05). Compared with sham operated rats, the mRNA expressions of MMP-8 and 13 were significantly increased by 54% - 183% in all three subgroups of AMI controls (all P < 0. 05 ) , and the mRNA expressions of MMP-8 and 13 in the 1-week and 4-week were significantly increased by 39% - 160% in these 3 subgroups ( all P < 0. 05 ) The mRNA and protein expressions of TIMP-1 were enhanced only in the 1-week subgroup of AMI controls by 104% and 67% respectively (both P <0. 05). The mRNA expression of TIMP-2 was significantly

关 键 词：强力霉素 大鼠 急性心肌梗死 基质金属蛋白酶 组织型抑制剂 AMI TIMP-1 

分 类 号：R542.22[医药卫生—心血管疾病]