基质金属蛋白酶与动脉粥样硬化斑块发生、发展的关系

目的利用高脂餐诱导的兔动脉粥样硬化模型,观察基质金属蛋白酶2(MMP_2)、MMP_2的调节因子MT1_MMP和MMP组织抑制因子_1(TIMP_1)、MMP_3、TIMP_3,在动脉粥样硬化发生和早期病变中的表达,以及在此过程中增生内膜降解基质的能力、胶原含量、内弹力板的变化;方法6周龄雄性新西兰大白兔(NZW),饲以高脂餐。在高脂餐前随机选取6只,取主动脉,液氮速冻,以后每隔2周随机选取8只,直至第10周。以免疫组化检测巨噬细胞、平滑肌细胞、MT1_MMP、MMP_2、TIMP_2、MMP_3、TIMP_3与COX_2的表达,检测组织原位明胶酶和酪蛋白酶活性。结果主动脉标本呈现5级动脉粥样硬化病变,高脂餐负荷时间与动脉粥样硬化病理分级正相关(相关系数:0.893,P<0.001)。主动脉内膜MT1_MMP.TIMP_2.MMP_2、MMP_3、TIMP_3随动脉粥样硬化进展表达逐渐增多,主动脉内膜降解明胶与酪蛋白的能力随动脉粥样硬化病变进展而增强,内膜胶原含量亦增加。内弹力板的破坏可见于Ⅱ-Ⅳ级斑块中,但有明显的个体差异。结论动脉粥样硬化发生和进展过程中,伴有MMPs激活,并有逐步增加的趋势,内膜胶原含量亦增加。内弹力板的稳定与否有明显的个体差异。

MT1 -MMP·TIMP-2·MMP-2, Proteolysis and Collagen Synthesis Are both Elevated during Atherogenesis in Cholesterol-Fed Rabbits

Objective Atherosclerosis has been linked to inappropriate vascular remodeling,which may result from the accumulation of inflammatory cells and the abnormal metabolism of extracellular matrix.It is presently unknown whether matrix metalloproteinases(MMPs) participate in the early pathological process.The aim of this study was to investigate whether MMPs are involved in atherogenesis in a cholesterol-fed rabbit model. Methods Forty-six New Zealand white rabbits were fed a diet containing 2% cholesterol and 3% lard.The rabbits were euthanized on day 0,and 8 after every 2 weeks to the end of 10th week.Aortic arch was excised and subjected to histological examination,immunohistochemistry and in situ zymography for MMPs and tissue inhibitor of matrix metalloproteinases(TIMPs).Atherosclerotic classification was according to AHA criteria.Results Based on HE staining,Sudan IV staining and macrophage immunostaining,the aortic arches were classified into five: normal artery(n8),initial lesion(n9),fatty streak (n8),preatheroma(n14) and atheroma(n7).During the progression of atherosclerosis,immunostained aortic slices showed that the triad membrane type 1-MMP(MT1-MMP),TIMP-2 and MMP-2,were colocalized with MMP-3 and TIMP-3,and increased in the hyperplastic intima concomitantly with elevated activities of gelatinolysis,caseinolysis,and migration of macrophages and smooth muscle cells.Conclusion During the early stages of atherogenesis,the modulation of MMPs is in a tendency towards activation,while collagen synthesis exceeds its degradation,which may contribute to the migration of macrophages and smooth muscle cells.