Author Matsusaka H, Ikeuchi M, Matsushima S, Ide T, Kubota T, Feldman AM, Takeshita A, Sunagawa K, Tsutsui H.
Title Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy.
Journal Am J Physiol Heart Circ Physiol
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.
Volume 289(5)
Pages H1858-64
Published 2005-11-1
DOI 10.1152/ajpheart.00216.2005
PII 00216.2005
PMID 15937097
MeSH Animals Cardiomyopathies / chemically induced* Cardiomyopathies / pathology* Cardiomyopathies / physiopathology Cytokines / biosynthesis Cytokines / genetics Cytokines / pharmacology* Electrocardiography Female Hemodynamics / physiology Male Matrix Metalloproteinase 2 / genetics* Mice Mice, Knockout Myocarditis / pathology* Myocarditis / physiopathology Myocardium / pathology Organ Size RNA, Messenger / biosynthesis RNA, Messenger / genetics Survival Analysis Tissue Inhibitor of Metalloproteinases / physiology Tumor Necrosis Factor-alpha / metabolism
IF 3.864
Times Cited 35
Mice RBRC00398