TIMP-3 deficiency leads to dilated cardiomyopathy.
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.
Fedak
Paul W M
PW
Division of Cardiac Surgery, University of Toronto, Toronto General Research Institute, Ontario, Canada.
Smookler
David S
DS
Kassiri
Zamaneh
Z
Ohno
Nobuhisa
N
Leco
Kevin J
KJ
Verma
Subodh
S
Mickle
Donald A G
DA
Watson
Katrina L
KL
Hojilla
Carlo V
CV
Cruz
William
W
Weisel
Richard D
RD
Li
Ren-Ke
RK
Khokha
Rama
R
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
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