Membrane-type 1 Matrix Metalloproteinase Regulates Macrophage-dependent Elastolytic Activity and Aneurysm Formation in Vivo
Membrane-type 1 Matrix Metalloproteinase Regulates Macrophage-dependent Elastolytic Activity and Aneurysm Formation in Vivo
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DOI：
10.1074/jbc.m806239200
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发表时间：
2009-01-16
影响因子：
4.8
通讯作者：
Baxter, Timothy
中科院分区：
文献类型：
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作者：
Xiong, Wanfen;Knispel, Rebecca;Baxter, Timothy
在动脉瘤形成过程中，膜锚定基质金属蛋白酶MT 1-MMP的水平显著升高。虽然MT 1-MMP主要由浸润的巨噬细胞表达，但该蛋白酶在体内腹主动脉瘤（AAA）形成中所起的作用仍不明确。使用新开发的AAA嵌合小鼠模型，我们现在证明巨噬细胞衍生的MT 1 MMP在疾病进展中起主导作用。在移植MT 1-MMP-null骨髓的野生型小鼠中，由CaCl 2应用于主动脉表面诱导的动脉瘤形成几乎完全消融。巨噬细胞浸润到主动脉介质不受MT 1-MMP缺失的影响，并且当MT 1-MMP+/+巨噬细胞而不是MT 1-MMP+/+淋巴细胞输注到MT 1-MMP-null骨髓受体中时，AAA形成可以重建。使用从WT/MT 1-MMP-/-嵌合小鼠、MMP-2缺失小鼠或MMP-9缺失小鼠中分离的巨噬细胞的体外研究表明，MT 1-MMP单独在巨噬细胞介导的弹性蛋白溶解中起主导作用。这些研究表明，AAA形成过程中弹性蛋白纤维网络的破坏依赖于巨噬细胞衍生的MT 1-MMP，其意外地充当巨噬细胞蛋白水解活性的直接作用调节剂。
During arterial aneurysm formation, levels of the membrane-anchored matrix metalloproteinase, MT1-MMP, are elevated dramatically. Although MT1-MMP is expressed predominately by infiltrating macrophages, the roles played by the proteinase in abdominal aortic aneurysm (AAA) formation in vivo remain undefined. Using a newly developed chimeric mouse model of AAA, we now demonstrate that macrophage-derived MT1MMP plays a dominant role in disease progression. In wild-type mice transplanted with MT1-MMP-null marrow, aneurysm formation induced by the application of CaCl2 to the aortic surface was almost completely ablated. Macrophage infiltration into the aortic media was unaffected by MT1-MMP deletion, and AAA formation could be reconstituted when MT1-MMP+/+ macrophages, but not MT1-MMP+/+ lymphocytes, were infused into MT1-MMP-null marrow recipients. In vitro studies using macrophages isolated from either WT/MT1-MMP-/- chimeric mice, MMP-2-null mice, or MMP-9-null mice demonstrate that MT1-MMP alone plays a dominant role in macrophage-mediated elastolysis. These studies demonstrate that destruction of the elastin fiber network during AAA formation is dependent on macrophage-derived MT1-MMP, which unexpectedly serves as a direct-acting regulator of macrophage proteolytic activity.