Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy

Hidenori Matsusaka, Masaki Ikeuchi, Shouji Matsushima, Tomomi Ide, Toru Kubota, Arthur M. Feldman, Akira Takeshita, Kenji Sunagawa, Hiroyuki Tsutsui

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Tumor necrosis factor-α (TNF-α) plays a pathophysiological role in the development and progression of heart failure. Matrix metalloproteinase (MMP)-2 is involved in extracellular matrix remodeling. Recent evidence suggests a protective role for this protease against tissue inflammation. Although MMP-2 is upregulated in the failing heart, little is known about its pathophysiological role. We thus hypothesized that ablation of the MMP-2 gene could affect cardiac remodeling and failure in TNF-α-induced cardiomyopathy. We crossed transgenic mice with cardiac-specific overexpression of TNF-α (TG) with MMP-2 knockout (KO) mice. Four groups of male and female mice were studied: wild-type (WT) with wild MMP-2 (WT/MMP+/+), WT with MMP-2 KO (WT/MMP-/-), TNF-α TG with wild MMP-2 (TG/MMP+/+), and TG with MMP-2 KO (TG/MMP-/-). The upregulation of MMP-2 zymographic activity in TG/MMP+/+ mice was completely abolished in TG/MMP-/- mice, and other MMPs and tissue inhibitors of metalloproteinase were comparable between groups. Survival was shorter for male TG/ MMP-/- than TG/MMP+/+ mice. Female TG/MMP-/- mice were more severely affected than TG/MMP+/+ mice with diminished cardiac function. Myocardial TNF-α and other proinflammatory cytokines were increased in TG/MMP+/+ mice, and this increase was similarly observed in TG/MMP-/- mice. The extent of myocardial infiltrating cells including macrophages was greater in TG/MMP -/- than in TG/MMP+/+ mice. Selective ablation of the MMP-2 gene reduces survival and exacerbates cardiac failure in association with the increased level of myocardial inflammation. MMP-2 may play a cardioprotective role in the pathogenesis of cytokine-induced cardiomyopathy.

Original languageEnglish
Pages (from-to)H1858-H1864
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume289
Issue number5 58-5
DOIs
Publication statusPublished - Nov 1 2005

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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