title: Altered expression of disintegrin metalloproteinases and their inhibitor in human dilated cardiomyopathy.
abstract: BACKGROUND
  Disintegrin metalloproteinases (ADAMs) may contribute to structural cardiac remodeling by altering cell-surface matrix receptors (integrins) and activating potent biomolecules. We compared expression of ADAMs, their endogenous inhibitor tissue inhibitor of metalloproteinases (TIMP)-3, and integrins in human heart tissue with varied patterns of structural remodeling.
  
  
  RESULTS
  Myocardium was obtained from patients with dilated cardiomyopathy (n=20), hypertrophic obstructive cardiomyopathy (n=5), and nonfailing donor hearts (n=7). Paired samples (n=10) were obtained before left ventricular assist device insertion and at transplantation. The expressions of ADAM10, ADAM12, ADAM15, and ADAM17, TIMP-3, and integrin receptors beta1D and beta3 were determined by quantitative immunoblotting. Integrin shedding was assessed by the ratio of integrin cleavage products to intact protein abundance. Confocal microscopy was performed. Dilated cardiomyopathy was characterized by increased ADAM10 and ADAM15 expression and reduced TIMP-3 expression. The integrin beta1D cleavage ratio was elevated, indicating receptor shedding. ADAM10 and ADAM15 expressions correlated with the cleavage ratio. ADAM10 colocalized with integrin beta1D by confocal microscopy. ADAM10 expression correlated with clinical indices of chamber dilatation and systolic dysfunction. Hemodynamic unloading reduced ADAM10 and ADAM12 expressions and increased integrin beta1D expression. ADAM12 and integrin beta1D expressions were increased in HOCM. ADAM17 was increased in both dilated cardiomyopathy and hypertrophic obstructive cardiomyopathy.
  
  
  CONCLUSIONS
  Disintegrin metalloproteinases are differentially expressed in human myocardium, reflecting the underlying pattern of structural remodeling. ADAM10 and ADAM15 may contribute to cardiac dilatation by reducing cell-matrix interactions via integrin shedding. Targeting disintegrin metalloproteinases, perhaps by restoring deficient TIMP-3 levels with gene or cell-based therapies, may prevent progressive chamber dilatation in human dilated cardiomyopathy.
authors.affiliation: General Research Institute, Division of Cardiac Surgery, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada. paul.fedak@utoronto.ca
authors.forename: Paul W M
authors.initials: PW
authors.lastname: Fedak
authors.forename: Christine S
authors.initials: CS
authors.lastname: Moravec
authors.forename: Patrick M
authors.initials: PM
authors.lastname: McCarthy
authors.forename: Svetlana M
authors.initials: SM
authors.lastname: Altamentova
authors.forename: Amy P
authors.initials: AP
authors.lastname: Wong
authors.forename: Marko
authors.initials: M
authors.lastname: Skrtic
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D051722:ADAM Proteins / Q000032:analysis* / Q000037:antagonists & inhibitors*; D000072197:ADAM10 Protein; D000072199:ADAM12 Protein; D000072198:ADAM17 Protein; D000293:Adolescent; D000328:Adult; D000368:Aged; D053829:Amyloid Precursor Protein Secretases; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015151:Immunoblotting; D019012:Integrin beta1 / Q000032:analysis; D039661:Integrin beta3 / Q000032:analysis; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000032:analysis*
chemical_list: D019012:Integrin beta1; D039661:Integrin beta3; D008565:Membrane Proteins; D011480:Protease Inhibitors; D019717:Tissue Inhibitor of Metalloproteinase-3; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; C098660:ADAM15 protein, human; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human