Transgenic expression of active MMP-2 in mice induced severe ventricular remodeling and markedly decreased left ventricular ejection fraction (48% vs 78% in controls; P=0.0006).
Does expression of active MMP-2 induce ventricular remodeling and systolic dysfunction in transgenic mice?
Expression of active MMP-2 in the heart is sufficient to directly induce severe ventricular remodeling and systolic dysfunction.
Absolute Event Rate: 48% vs 78%
p-value: p=0.0006
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.
Bergman et al. (Sat,) conducted a other in Ventricular remodeling and systolic dysfunction. Transgenic expression of active MMP-2 vs. Control was evaluated on Left ventricular ejection fraction (p=0.0006). Transgenic expression of active MMP-2 in mice induced severe ventricular remodeling and markedly decreased left ventricular ejection fraction (48% vs 78% in controls; P=0.0006).
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