title: Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy.
abstract: Tumor necrosis factor-alpha (TNF-alpha) 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-alpha-induced cardiomyopathy. We crossed transgenic mice with cardiac-specific overexpression of TNF-alpha (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-alpha 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-alpha 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.
authors.affiliation: Dept. of Cardiovascular Medicine, Kyushu Imoversotu Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Matsusaka
authors.forename: Masaki
authors.initials: M
authors.lastname: Ikeuchi
authors.forename: Shouji
authors.initials: S
authors.lastname: Matsushima
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
authors.forename: Akira
authors.initials: A
authors.lastname: Takeshita
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D004562:Electrocardiography; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016019:Survival Analysis; D019714:Tissue Inhibitor of Metalloproteinases / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2