Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload

Hidenori Matsusaka, Tomomi Ide, Shoji Matsushima, Masaki Ikeuchi, Toru Kubota, Kenji Sunagawa, Shintaro Kinugawa, Hiroyuki Tsutsui

Research output: Contribution to journalArticle

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Abstract

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 μm2; 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.

Original languageEnglish
Pages (from-to)711-717
Number of pages7
JournalHypertension
Volume47
Issue number4
DOIs
Publication statusPublished - Apr 1 2006

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Matrix Metalloproteinase 2
Constriction
Pressure
Matrix Metalloproteinases
Matrix Metalloproteinase 1
Weights and Measures
Hypertrophy
Body Weight
Blood Pressure
Matrix Metalloproteinase 3
Tissue Inhibitor of Metalloproteinase-1
Matrix Metalloproteinase 9
Cardiomegaly
Left Ventricular Dysfunction
Left Ventricular Hypertrophy
Knockout Mice
Muscle Cells
Extracellular Matrix
Heart Diseases
Arterial Pressure

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. / Matsusaka, Hidenori; Ide, Tomomi; Matsushima, Shoji; Ikeuchi, Masaki; Kubota, Toru; Sunagawa, Kenji; Kinugawa, Shintaro; Tsutsui, Hiroyuki.

In: Hypertension, Vol. 47, No. 4, 01.04.2006, p. 711-717.

Research output: Contribution to journalArticle

Matsusaka, Hidenori ; Ide, Tomomi ; Matsushima, Shoji ; Ikeuchi, Masaki ; Kubota, Toru ; Sunagawa, Kenji ; Kinugawa, Shintaro ; Tsutsui, Hiroyuki. / Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. In: Hypertension. 2006 ; Vol. 47, No. 4. pp. 711-717.
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AU - Kinugawa, Shintaro

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