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

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

Research output: Contribution to journalArticle

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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
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume289
Issue number5 58-5
DOIs
Publication statusPublished - Nov 1 2005

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Matrix Metalloproteinase 2
Matrix Metalloproteinases
Cardiomyopathies
Cytokines
Inflammation
Genes
Tumor Necrosis Factor-alpha
Heart Failure
Tissue Inhibitor of Metalloproteinases
Matrix Metalloproteinase Inhibitors
Knockout Mice
Transgenic Mice
Extracellular Matrix
Peptide Hydrolases
Up-Regulation

All Science Journal Classification (ASJC) codes

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

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Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy. / Matsusaka, Hidenori; Ikeuchi, Masaki; Matsushima, Shoji; Ide, Tomomi; Kubota, Toru; Feldman, Arthur M.; Takeshita, Akira; Sunagawa, Kenji; Tsutsui, Hiroyuki.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 289, No. 5 58-5, 01.11.2005.

Research output: Contribution to journalArticle

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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.",
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AU - Ikeuchi, Masaki

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AU - Ide, Tomomi

AU - Kubota, Toru

AU - Feldman, Arthur M.

AU - Takeshita, Akira

AU - Sunagawa, Kenji

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