title: TIMP-3 deficiency leads to dilated cardiomyopathy.
abstract: 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.
  
  
  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.
authors.affiliation: Division of Cardiac Surgery, University of Toronto, Toronto General Research Institute, Ontario, Canada.
authors.forename: Paul W M
authors.initials: PW
authors.lastname: Fedak
authors.forename: David S
authors.initials: DS
authors.lastname: Smookler
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Ohno
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Leco
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
authors.forename: Donald A G
authors.initials: DA
authors.lastname: Mickle
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Watson
authors.forename: Carlo V
authors.initials: CV
authors.lastname: Hojilla
authors.forename: William
authors.initials: W
authors.lastname: Cruz
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003094:Collagen / Q000032:analysis; D018450:Disease Progression; D005109:Extracellular Matrix / Q000737:chemistry; D006706:Homeostasis; D006984:Hypertrophy; D008264:Macrophages / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D008666:Metalloendopeptidases / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000473:pathology; D009573:Nitrites / Q000032:analysis; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000032:analysis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014463:Ultrasonography
chemical_list: D009573:Nitrites; D047889:Receptors, Tumor Necrosis Factor, Type II; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein