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1 Kyushu University Graduate School of Medical Sciences, Department of Cardiovascular Medicine, Fukuoka, Japan
2 Jefferson Medical College, Department of Medicine, Philadelphia, PA, USA
3 Hokkaido University Graduate School of Medicine, Department of Cardiovascular Medicine, Sapporo, Japan
* To whom correspondence should be addressed. E-mail: htsutsui{at}med.hokudai.ac.jp.
Tumor necrosis factor-
(TNF-) plays a pathophysiological role in the development and progression of heart failure. Matrix metalloproteinase-2 (MMP-2) is involved in the extracellular matrix remodeling. Recent evidence suggests, however, a protective role against tissue inflammation for this protease. Although MMP-2 is upregulated in the failing heart, little is known about its pathophysiological role. We thus hypothesized that the ablation of 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 KO (TG/MMP-/-). The upregulation of MMP-2 zymographic activity seen in TG/MMP+/+ was completely abolished in TG/MMP-/-, and other MMPs and TIMPs were comparable between groups. The survival of male TG/MMP-/- was worse than that of TG/MMP+/+. Female TG/MMP-/- were more severely affected than TG/MMP+/+ with diminished cardiac function. Myocardial TNF- and other proinflammatory cytokines were increased in TG/MMP+/+ and this increase was similarly observed in TG/MMP-/-. The extent of myocardial infiltrating cells including macrophages was greater in TG/MMP-/- than in TG/MMP+/+. Selective ablation of 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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