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This Article Full Text Full Text (PDF) All Versions of this Article: 289/5/H1858    most recent 00216.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Matsusaka, H. Articles by Tsutsui, H. Search for Related Content PubMed PubMed Citation Articles by Matsusaka, H. Articles by Tsutsui, H.

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

¹Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka; ³Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and ²Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania

Submitted 7 March 2005 ; accepted in final form 23 May 2005

Tumor necrosis factor- (TNF-) 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--induced cardiomyopathy. We crossed transgenic mice with cardiac-specific overexpression of TNF- (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- 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- 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.

metalloproteinases; heart failure; tumor necrosis factor

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