This Article Full Text Full Text (PDF) All Versions of this Article: 47/4/711    most recent 01.HYP.0000208840.30778.00v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matsusaka, H. Articles by Tsutsui, H. Search for Related Content PubMed PubMed Citation Articles by Matsusaka, H. Articles by Tsutsui, H. Related Collections Structure Hypertrophy Myocardial cardiomyopathy disease Remodeling Animal models of human disease Gene expression Genetically altered mice Related Article

(Hypertension. 2006;47:711.)
© 2006 American Heart Association, Inc.

Original Articles

Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload

Hidenori Matsusaka; Tomomi Ide; Shouji Matsushima; Masaki Ikeuchi; Toru Kubota; Kenji Sunagawa; Shintaro Kinugawa; Hiroyuki Tsutsui

From the Department of Cardiovascular Medicine (H.M., T.I., S.M., M.I., T.K., K.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka; and Department of Cardiovascular Medicine (S.K., H.T.), Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Correspondence to Hiroyuki Tsutsui, Dept of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan. E-mail htsutsui{at}med.hokudai.ac.jp

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.

Key Words: hypertrophy • heart failure • fibrosis • extracellular matrix • hypertension, experimental • myocardium

Related Article:

Matrix Reloaded: The Matrix Metalloproteinase Paradox

Anna N. Panek and Michael Bader
Hypertension 2006 47: 640-641. [Full Text] [PDF]

This article has been cited by other articles:

				L. Vinet, P. Rouet-Benzineb, X. Marniquet, N. Pellegrin, L. Mangin, L. Louedec, J.-L. Samuel, and J.-J. Mercadier Chronic doxycycline exposure accelerates left ventricular hypertrophy and progression to heart failure in mice after thoracic aorta constriction Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H352 - H360. [Abstract] [Full Text] [PDF]

				F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]

				N. K. LeBrasseur, T.-A. S. Duhaney, D. S. De Silva, L. Cui, P. C. Ip, L. Joseph, and F. Sam Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension Hypertension, September 1, 2007; 50(3): 489 - 496. [Abstract] [Full Text] [PDF]

				T.-A. S. Duhaney, L. Cui, M. K. Rude, N. K. Lebrasseur, S. Ngoy, D. S. De Silva, D. A. Siwik, R. Liao, and F. Sam Peroxisome Proliferator-Activated Receptor {alpha}-Independent Actions of Fenofibrate Exacerbates Left Ventricular Dilation and Fibrosis in Chronic Pressure Overload Hypertension, May 1, 2007; 49(5): 1084 - 1094. [Abstract] [Full Text] [PDF]

				P. Krishnamurthy, V. Subramanian, M. Singh, and K. Singh {beta}1 Integrins Modulate {beta}-Adrenergic Receptor-Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling Hypertension, April 1, 2007; 49(4): 865 - 872. [Abstract] [Full Text] [PDF]

				R. Martos, J. Baugh, M. Ledwidge, C. O'Loughlin, C. Conlon, A. Patle, S. C. Donnelly, and K. McDonald Diastolic Heart Failure: Evidence of Increased Myocardial Collagen Turnover Linked to Diastolic Dysfunction Circulation, February 20, 2007; 115(7): 888 - 895. [Abstract] [Full Text] [PDF]

				A. N. Panek and M. Bader Matrix Reloaded: The Matrix Metalloproteinase Paradox Hypertension, April 1, 2006; 47(4): 640 - 641. [Full Text] [PDF]