Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice
Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice
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DOI：
10.1172/jci200522304
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发表时间：
2005-03-01
影响因子：
15.9
通讯作者：
Okada, Y
中科院分区：
文献类型：
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作者：
Matsumura, S;Iwanaga, S;Okada, Y
基质金属蛋白酶与急性心肌梗死后左室重构有关。为了分析MMP-2的作用，我们通过结扎MMP-2-KO和WT小鼠的左冠状动脉来产生MI，后者口服MMP-2选择性抑制剂或载体（TISAM）。MMP-2-KO和TISAM处理的小鼠的存活率显著高于对照WT小鼠。对照WT小鼠中死亡的主要原因是心脏破裂，这在MMP-2-KO或TISAM处理的小鼠中未观察到。对照WT小鼠，而不是MMP-2-KO或TISAM处理的小鼠，显示出MMP-2的酶原的活化、强的明胶分解活性和ECM组分的降解，包括梗死心肌中的层粘连蛋白和纤连蛋白。尽管对照WT小鼠中的梗死心肌细胞被巨噬细胞迅速清除，但MMP-2-KO和TISAM处理的小鼠中的清除受到抑制。巨噬细胞迁移由来自对照WT小鼠的梗死心肌组织诱导，并且在迁移测定之前通过用层粘连蛋白或纤连蛋白肽处理巨噬细胞来抑制。这些数据表明，MMP-2活性的抑制通过防止心脏破裂改善急性MI后的存活率，并通过减少巨噬细胞浸润延迟MI后重塑。
MMPs are implicated in LV remodeling after acute myocardial infarction (MI). To analyze the role of MMP-2, we generated MI by ligating the left coronary artery of MMP-2-KO and WT mice, the latter of which were administered orally an MMP-2-selective inhibitor or vehicle (TISAM). The survival rate was significantly higher in MMP-2-KO and TISAM-treated mice than in control WT mice. The main cause of mortality in control WT mice was cardiac rupture, which was not observed in MMP-2-KO or TISAM-treated mice. Control WT mice, but not MMP-2-KO or TISAM-treated mice, showed activation of the zymogen of MMP-2, strong gelatinolytic activity, and degradation of ECM components, including laminin and fibronectin, in the infarcted myocardium. Although infarcted cardiomyocytes in control WT mice were rapidly removed by macrophages, the removal was suppressed in MMP-2-KO and TISAM-treated mice. Macrophage migration was induced by the infarcted myocardial tissue from control WT mice and was inhibited by treatment of macrophages with laminin or fibronectin peptides prior to migration assay. These data suggest that inhibition of MMP-2 activity improves the survival rate after acute MI by preventing cardiac rupture and delays post-Ml remodeling through a reduction in macrophage infiltration.