Published online before print July 19, 2004, doi: 10.1161/01.CIR.0000134959.83967.2D
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(Circulation. 2004;110:2401-2409.)
© 2004 American Heart Association, Inc.
Heart Failure |
TIMP-3 Deficiency Leads to Dilated Cardiomyopathy
From the Division of Cardiac Surgery, University of Toronto, Toronto General Research Institute (P.W.M.F., N.O., S.V., D.A.G.M., R.D.W., R.L.), and Ontario Cancer Institute, University of Toronto, University Health Network, Toronto (D.S.S., Z.K., K.L.W., C.V.H., W.C., R.K.), and the University of Western Ontario, London (K.J.L.), Ontario, Canada.
Correspondence to R. Khokha, Ontario Cancer Institute, 610 University Ave, Toronto, Ontario M5G 2M9, Canada. E-mail rkhokha{at}uhnres.utoronto.ca
Received October 24, 2003; de novo received May 5, 2004; revision received May 24, 2004; accepted May 25, 2004.
Background— Despite the mounting clinical burden of heart failure, the biomolecules that control myocardial tissue remodeling are poorly understood. TIMP-3 is an endogenous inhibitor of matrix metalloproteinases (MMPs) that has been found to be deficient in failing human myocardium. We hypothesized that TIMP-3 expression prevents maladaptive tissue remodeling in the heart, and accordingly, its deficiency in mice would alone be sufficient to trigger progressive cardiac remodeling and dysfunction similar to human heart failure.
Methods and Results— Mice with a targeted timp-3 deficiency were evaluated with aging and compared with age-matched wild-type littermates. Loss of timp-3 function triggered spontaneous LV dilatation, cardiomyocyte hypertrophy, and contractile dysfunction at 21 months of age consistent with human dilated cardiomyopathy. Its absence also resulted in interstitial matrix disruption with elevated MMP-9 activity, and activation of the proinflammatory tumor necrosis factor-
cytokine system, molecular hallmarks of human myocardial remodeling.
Conclusions— TIMP-3 deficiency disrupts matrix homeostasis and the balance of inflammatory mediators, eliciting the transition to cardiac dilation and dysfunction. Therapeutic restoration of myocardial TIMP-3 may provide a novel approach to limit cardiac remodeling and the progression to failure in patients with dilated cardiomyopathy.
Key Words: remodeling • cardiomyopathy • metalloproteinases • inhibitors
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