title: Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction.
abstract: 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 alpha-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 microl; P = 0.003] and systolic (C 7 +/- 2 vs. MMP 28 +/- 14 microl; P = 0.003) left ventricular (LV) volumes and relatively preserved stroke volume (C 26 +/- 4 vs. MMP 23 +/- 3 microl; 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/microl(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.
authors.affiliation: Department of Medicine, San Francisco Department of Veterans Affairs Medical Center/University of California, San Francisco, California 94121, USA.
authors.forename: Marina R
authors.initials: MR
authors.lastname: Bergman
authors.forename: John R
authors.initials: JR
authors.lastname: Teerlink
authors.forename: Rajeev
authors.initials: R
authors.lastname: Mahimkar
authors.forename: Luyi
authors.initials: L
authors.lastname: Li
authors.forename: Bo-Qing
authors.initials: BQ
authors.lastname: Zhu
authors.forename: Anita
authors.initials: A
authors.lastname: Nguyen
authors.forename: Sia
authors.initials: S
authors.lastname: Dahi
authors.forename: Joel S
authors.initials: JS
authors.lastname: Karliner
authors.forename: David H
authors.initials: DH
authors.lastname: Lovett
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003971:Diastole / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D013599:Systole / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D019210:Troponin I / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D019210:Troponin I; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14