TIMP-3 deficiency leads to dilated cardiomyopathy

被引:150
作者
Fedak, PWM
Smookler, DS
Kassiri, Z
Ohno, N
Leco, KJ
Verma, S
Mickle, DAG
Watson, KL
Hojilla, CV
Cruz, W
Weisel, RD
Li, RK
Khokha, R
机构
[1] Univ Toronto, Univ Hlth Network, Ontario Canc Inst, Toronto, ON M5G 2M9, Canada
[2] Univ Toronto, Toronto Gen Res Inst, Div Cardiac Surg, Toronto, ON, Canada
[3] Univ Western Ontario, London, ON, Canada
关键词
remodeling; cardiomyopathy; metalloproteinases; inhibitors;
D O I
10.1161/01.CIR.0000134959.83967.2D
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-alpha 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.
引用
收藏
页码:2401 / 2409
页数:9
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