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

1 Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California, San Francisco and 2 Cardiovascular 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/µl 2 ; 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 Address for reprint requests and other correspondence: D. H. Lovett, Dept. of Medicine (111J), San Francisco Department of Veterans Affairs Medical Center/Univ. of California San Francisco, 4150 Clement St., San Francisco, CA 94121 (e-mail: david.lovett{at}med.va.gov )