Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice
Shin-ichiro Matsumura, Shiro Iwanaga, Satsuki Mochizuki, Hiroyuki Okamoto, Satoshi Ogawa, Yasunori Okada
Shin-ichiro Matsumura, Shiro Iwanaga, Satsuki Mochizuki, Hiroyuki Okamoto, Satoshi Ogawa, Yasunori Okada
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Article Cardiology

Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice

Abstract

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-MI remodeling through a reduction in macrophage infiltration.

Authors

Shin-ichiro Matsumura, Shiro Iwanaga, Satsuki Mochizuki, Hiroyuki Okamoto, Satoshi Ogawa, Yasunori Okada

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Figure 9

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Demonstration of the degradation of laminin and fibronectin by immunoblo...
Demonstration of the degradation of laminin and fibronectin by immunoblotting. Supernatants of infarcted myocardial tissue homogenates were prepared from vehicle-treated WT mice (lane 2), TISAM-treated mice (lane 3), and MMP-2–KO mice (lane 4), subjected to SDS-PAGE, and immunoblotted for laminin (A) and fibronectin (B) as described in Methods. Sham-operated noninfarcted myocardium (lane 1) was also immunoblotted. Note the marked degradation of laminin and fibronectin in infarcted myocardium from vehicle-treated control WT mice, which was almost completely inhibited in TISAM-treated and MMP-2–KO mice. α, β, and γ chains of laminin and intact fibronectin of 240 kDa are indicated by arrows. The arrowhead denotes a fibronectin fragment of 120 kDa. Immunoblotting for β-actin was used to show the similar amount of sample application to each lane.