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Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction.
Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2007 Apr; Vol. 292 (4), pp. H1847-60. Date of Electronic Publication: 2006 Dec 08. - Publication Year :
- 2007
-
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.
- Subjects :
- Animals
COS Cells
Chlorocebus aethiops
Diastole physiology
Fibroblasts cytology
Fibroblasts enzymology
Gene Expression Regulation, Enzymologic
Matrix Metalloproteinase 13 metabolism
Matrix Metalloproteinase 14 metabolism
Matrix Metalloproteinase 9 metabolism
Mice
Mice, Transgenic
Myocardium pathology
Rats
Transcription, Genetic physiology
Troponin I metabolism
Ventricular Dysfunction metabolism
Ventricular Dysfunction pathology
Matrix Metalloproteinase 2 genetics
Matrix Metalloproteinase 2 metabolism
Myocardium enzymology
Systole physiology
Ventricular Dysfunction physiopathology
Ventricular Remodeling physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0363-6135
- Volume :
- 292
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 17158653
- Full Text :
- https://doi.org/10.1152/ajpheart.00434.2006