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 10

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Macrophage migration in response to infarcted myocardium (A), laminin an...
Macrophage migration in response to infarcted myocardium (A), laminin and fibronectin peptides (B), inhibition of migration activity to infarcted myocardium by laminin and fibronectin peptides (C), and digestion products of laminin and fibronectin by MMP-2 (D). (A) Migration activity of macrophages derived from WT and MMP-2–KO mice in response to infarcted myocardium from vehicle-treated WT (Infarct), TISAM-treated (TISAM infarct), and MMP-2–KO mice (KO infarct). As for controls, myocardium from sham-operated WT mice (Sham) and from noninfarct areas of infarcted vehicle-treated WT mice (Noninfarct) was used. HPF, high-power field. ***P < 0.001. (B) Migration activity of macrophages from WT mice in response to laminin peptides (LGTIPG and YIGSR) and intact laminin (Ln) and fibronectin peptides (RGDS and RGES) and intact fibronectin (Fn). (C) Inhibition of WT macrophage migration activity to infarcted myocardium or fMLP by laminin and fibronectin peptides. Macrophages were incubated with buffer alone (None), laminin peptides, or fibronectin peptides and then subjected to a migration assay by the addition of infarcted myocardium from WT mice or fMLP to lower chambers. Control, GBSS-BSA alone in lower chambers. ***P < 0.001. (D) Macrophage migration in response to MMP-2 digestion products of laminin and fibronectin. Macrophages were incubated with buffer alone, laminin, or fibronectin peptides and then subjected to a migration assay by the addition of the digestion products to lower chambers. Control, Ln, and Fn represent GBSS-BSA alone, laminin alone, and fibronectin alone in lower chambers, respectively. Digestion patterns of laminin and fibronectin on SDS-PAGE are shown. *P < 0.05; **P < 0.01.