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Am J Physiol Heart Circ Physiol (December 8, 2006). doi:10.1152/ajpheart.00434.2006
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Submitted on May 1, 2006
Accepted on November 27, 2006

Cardiac Matrix Metalloproteinase-2 Expression Independently Induces Marked Ventricular Remodeling and Systolic Dysfunction

Marina Berman1, John Teerlink2, Luyi Li1, Rajeev Mahimkar1, Bo-Qing Zhu1, Anita Nguyen1, Sia Dahi1, Joel Karliner3, and David H. Lovett4*

1 Medicine/SFVAMC, University of California, San Francisco, San Francisco, California, United States
2 Medicine/SFVAMC, University of California, San Francisco, San Francisco, California, United States; Medicine, UCSF, United States
3 Medicine/SFVAMC, University of California, San Francisco, San Francisco, California, United States; V. A. Medical Center, Cardiology Dept. - 111-C8, San Francisco, California, United States
4 Nephrology Section (111J), V.A. Medical Center, San Francisco, California, United States

* To whom correspondence should be addressed. E-mail: david.lovett{at}med.va.gov.

Although enhanced cardiac matrix metalloproteinase-2 (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 {alpha}-myosin heavy chain promoter. At 4 months 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 month 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 MT1-MMP. Increases in diastolic (C, 33 ± 3 vs. MMP, 51 ± 12 µl; p=0.003) and systolic (C, 7 ± 2 vs. MMP, 28 ± 14 µl; p=0.003) 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 mWatts/µl2; p=0.0003) and decreased end-systolic pressure volume relation (Eea; 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.




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