Divergent effects of matrix metalloproteinase-3, metalloproteinase-7, metalloproteinase-9, and metalloproteinase-12 on atherosclerotic plaque stability in mouse brachiocephalic arteries
Divergent effects of matrix metalloproteinase-3, metalloproteinase-7, metalloproteinase-9, and metalloproteinase-12 on atherosclerotic plaque stability in mouse brachiocephalic arteries
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DOI：
10.1073/pnas.0506201102
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发表时间：
2005-10-25
影响因子：
11.1
通讯作者：
Jackson, CL
中科院分区：
文献类型：
--
作者：
Johnson, JL;George, SJ;Jackson, CL
基质金属蛋白酶（MMPs）被认为参与动脉粥样硬化病变的生长、不稳定和最终破裂。使用小鼠头臂动脉斑块不稳定模型，我们比较了载脂蛋白E（apoE）/MMP-3，apoE/MMP-7，apoE/MMP-9和apoE/MMP-12双敲除与年龄，品系和性别匹配的apoE单敲除对照。apoE/MMP-3和apoE/MMP-9双基因敲除组的头臂动脉斑块明显大于对照组。在双敲除中，埋藏的纤维层的数量也显著更高，并且两种敲除均表现出指示不稳定斑块表型的细胞组成变化。相反，与对照组相比，apoE/MMP-12双敲除组的病变大小和埋藏的纤维层减少，双敲除组斑块中平滑肌细胞增加，巨噬细胞含量减少，表明斑块表型稳定。ApoE/MMP-7双基因敲除斑块中的平滑肌细胞显著多于对照组，但这些动物的病变大小和稳定性均未发生改变。因此，MMP-3和MMP-9似乎通常发挥保护作用，限制斑块生长并促进稳定的斑块表型。MMP-12支持病变扩张和不稳定。MMP-7对斑块生长或稳定性没有影响，尽管它与斑块中平滑肌细胞含量减少有关。这些数据表明，基质金属蛋白酶直接参与动脉粥样硬化斑块的不稳定，并清楚地表明，MMP家族的成员有广泛不同的影响动脉粥样硬化。
Matrix metalloproteinases (MMPs) are thought to be involved in the growth, destabilization, and eventual rupture of atherosclerotic lesions. Using the mouse brachiocephalic artery model of plaque instability, we compared apolipoprotein E (apoE)/MMP-3, apoE/MMP-7, apoE/MMP-9, and apoE/MMP-12 double knockouts with their age-, strain-, and sex-matched apoE single knockout controls. Brachlocephalic artery plaques were significantly larger in apoE/MMP-3 and apoE/MMP-9 double knockouts than in controls. The number of buried fibrous layers was also significantly higher in the double knockouts, and both knockouts exhibited cellular compositional changes indicative of an unstable plaque phenotype. Conversely, lesion size and buried fibrous layers were reduced in apoE/MMP-12 double knockouts compared with controls, and double knockouts had increased smooth muscle cell and reduced macrophage content in the plaque, indicative of a stable plaque phenotype. ApoE/MMP-7 double knockout plaques contained significantly more smooth muscle cells than controls, but neither lesion size nor features of stability were altered in these animals. Hence, MMP-3 and MMP-9 appear normally to play protective roles, limiting plaque growth and promoting a stable plaque phenotype. MMP-12 supports lesion expansion and destabilization. MMP-7 has no effect on plaque growth or stability, although it is associated with reduced smooth muscle cell content in plaques. These data demonstrate that MMPs are directly involved in atherosclerotic plaque destabilization and clearly show that members of the MMP family have widely differing effects on atherogenesis.