MMPs及TIMPs在兔血管再狭窄中的表达及复方丹参滴丸预防再狭窄的作用机制

The expressions of matrix metalloproteinase and its inhibitor in blood vessel restenosis of rabbits and the preventive effect of composite danshen pill on restenosis

目的研究兔髂动脉成形术后血管内膜增生和基质金属蛋白酶（MMPs）及其抑制物（TIMPs）表达之间的关系，探讨复方丹参滴丸预防再狭窄的可能机制。方法健康成年二级雄性日本大耳白兔30只，平均体重2．5—3．0kg。随机分为3组：正常对照组10只，模型组10只（球囊内膜剥脱加高胆固醇饮食），治疗组10只（球囊内膜剥脱加高胆固醇饮食以及复方丹参滴丸150mg／d）。结果兔髂动脉造影、血管病理图像分析检测结果：①复方丹参滴丸组较模型组血管造影示管腔直径狭窄、内膜厚度减少、内膜面积减少、内膜厚度和中膜厚度比、面积比，各组之间有显著性差异（P〈0．01）。②免疫组化分析：模型组MMP-2、MMP-9、TIMP1、TIMP2表达均高于对照组（P〈0．01）；复方丹参滴丸组MMP-2、MMP-9的表达低于模型组，而TIMP1、TIMP2的表达高于模型组；TIMP1／MMP-2、TIMP2／MMP-9明显增加，差异有显著性（P〈0．01）。③内膜的增生以及管腔的狭窄程度与MMP-2、MMP-9有很好的相关性（r=0．896，P〈0．01）。结论MMP和TIMP在再狭窄形成中起重要作用；复方丹参滴丸能够明显抑制血管损伤后的内膜增生，可能的机制足通过影响金属蛋门酶MMP-2、MMP-9及其抑制物TIMP1、TIMP2的表达从而抑制胶原的生成、平滑肌的迁移、增生，而减少内膜的增生。

Objective To study the relationship of endangium proliferation and the expression of metalloproteinases （MMPs） and tissue inhibitors of metalloproteinases （TIMPs） ＇after angioplasty of iliac artery in rabbits to investigate the probable mechanism of composite Danshen pill （CDP） in prevention and treatment of restenosis. Methods 30 white male rabbits of Japan （ the average body weight was 2.5 - 3.0 kg. ） were randomly divided into 3 groups ： normal control group, model group （intima destroyed by balloon and given hypercholesterol diet）, CDP group （intima destroyed by balloon and given hypercholesterol diet plus drug CDP 150 mg/d）, 10 ones each group. Results The results of iliac artery angiogram and the analysis of pathology：there were lumens stenosis, thinner intima, smaller intima area, in CDP group compared with those in model group,and ratio of intima and tunica media thickness and area among each group （P 〈0. 01 ）. Immunohistochemistry analysis：the MMP-2, M MP-9, TIMP1 ,T IMP2 in model group significantly increased than those in control group （P 〈 0. 01 ）. The CDP group had lower MMP-2 and MMP-9 expression, higher TIMP1 and TIMP2 expression, and increased MMP2/TIMP1, MMP9/TIMP2 than model group （P 〈 0. 01 ）. The thickening of vascular neointima and stenosis degree of vascular lumen were relevant to MMP-2 and MMP- 9 （ r = 0. 896, P 〈 0. 01 ）. Conclusions MMP and TIMP play the very important role in the restenosis process of artery. CDP could inhibit the thickness of vascular neointima after balloon injury,the probable mechanism of which may be inhibiting collagen formation, smooth muscle immigration and decreasing hyperplasia of intima by interfering expression of MMPs and TIMPs.