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This Article Full Text Full Text (PDF) All Versions of this Article: 292/4/H1847    most recent 00434.2006v1 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 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 Web of Science (21) Citing Articles via Google Scholar Google Scholar Articles by Bergman, M. R. Articles by Lovett, D. H. Search for Related Content PubMed PubMed Citation Articles by Bergman, M. R. Articles by Lovett, D. H.

Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction

¹Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California, San Francisco and ²Cardiovascular Research Institute, University of California, San Francisco, California

Submitted 1 May 2006 ; accepted in final form 27 November 2006

Although enhanced cardiac matrix metalloproteinase (MMP)-2 synthesis has been associated with ventricular remodeling and failure, whether MMP-2 expression is a direct mediator of this process is unknown. We generated transgenic mice expressing active MMP-2 driven by the -myosin heavy chain promoter. At 4 mo MMP-2 transgenic hearts demonstrated expression of the MMP-2 transgene, myocyte hypertrophy, breakdown of Z-band registration, lysis of myofilaments, disruption of sarcomere and mitochondrial architecture, and cardiac fibroblast proliferation. Hearts from 8-mo-old transgenic mice displayed extensive myocyte disorganization and dropout with replacement fibrosis and perivascular fibrosis. Older transgenic mice also exhibited a massive increase in cardiac MMP-2 expression, representing recruitment of endogenous MMP-2 synthesis, with associated expression of MMP-9 and membrane type 1 MMP. Increases in diastolic [control (C) 33 ± 3 vs. MMP 51 ± 12 µl; P = 0.003] and systolic (C 7 ± 2 vs. MMP 28 ± 14 µl; P = 0.003) left ventricular (LV) volumes and relatively preserved stroke volume (C 26 ± 4 vs. MMP 23 ± 3 µl; P = 0.16) resulted in markedly decreased LV ejection fraction (C 78 ± 7% vs. MMP 48 ± 16%; P = 0.0006). Markedly impaired systolic function in the MMP transgenic mice was demonstrated in the reduced preload-adjusted maximal power (C 240 ± 84 vs. MMP 78 ± 49 mW/µl²; P = 0.0003) and decreased end-systolic pressure-volume relation (C 7.5 ± 1.5 vs. MMP 4.7 ± 2.0; P = 0.016). Expression of active MMP-2 is sufficient to induce severe ventricular remodeling and systolic dysfunction in the absence of superimposed injury.

heart failure; fibrosis; mitochondria; sarcomere

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