Targeted deletion of MMP 2 in mice with chronic pressure overload significantly reduced LV weight/body weight (4.2 vs 5.0 mg/g; P<0.01) and interstitial fibrosis compared to wild-type mice.
Does targeted deletion of the MMP 2 gene ameliorate pressure overload-induced cardiac hypertrophy and dysfunction in mice?
Targeted deletion of MMP 2 in mice ameliorates pressure overload-induced left ventricular hypertrophy, dysfunction, and interstitial fibrosis, suggesting MMP 2 inhibition as a potential therapeutic strategy for hypertensive heart disease.
Absolute Event Rate: 4.2% vs 5%
p-value: p=<0.01
Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload (PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction (TAC) in male MMP 2 knockout (KO) mice (n=10) and sibling wild-type (WT) mice (n=9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.4-fold increased in WT+TAC, and this increase was not observed in KO+TAC, with no significant alterations in other MMPs (MMP 1, 3, 8, and 9) or tissue inhibitors of MMPs (1, 2, 3, and 4). TAC resulted in a significant increase in left ventricular (LV) weight and LV end-diastolic pressure (EDP) with preserved systolic function. KO+TAC mice exerted significantly lower LV weight/body weight (4.2+/-0.2 versus 5.0+/-0.2 mg/g; P<0.01), lung weight/body weight (4.9+/-0.2 versus 6.2+/-0.4 mg/g; P<0.01), and LV end-diastolic pressure (4+/-1 versus 10+/-2 mm Hg; P<0.05) than WT+TAC mice despite comparable aortic pressure. KO+TAC mice had less myocyte hypertrophy (cross-sectional area; 322+/-14 versus 392+/-14 microm2; P<0.01) and interstitial fibrosis (collagen volume fraction; 3.3+/-0.5 versus 8.2+/-1.0%; P<0.01) than WT+TAC mice. MMP 2 plays an important role in PO-induced LV hypertrophy and dysfunction. The inhibition of MMP 2 activation may, therefore, be a useful therapeutic strategy to manage hypertensive heart disease.
Matsusaka et al. (Tue,) conducted a other in Chronic pressure overload and myocardial remodeling (n=19). Targeted deletion of MMP 2 gene vs. Wild-type (WT) mice was evaluated on Left ventricular (LV) weight/body weight (mg/g) (p=<0.01). Targeted deletion of MMP 2 in mice with chronic pressure overload significantly reduced LV weight/body weight (4.2 vs 5.0 mg/g; P<0.01) and interstitial fibrosis compared to wild-type mice.
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