Published online before print January 9, 2006, doi: 10.1161/CIRCULATIONAHA.105.571414
(Circulation. 2006;113:238-245.)
© 2006 American Heart Association, Inc.
Heart Failure |
Altered Expression of Disintegrin Metalloproteinases and Their Inhibitor in Human Dilated Cardiomyopathy
From the Toronto General Research Institute, Division of Cardiac Surgery, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada (P.W.M.F., S.M.A., A.P.W., M.S., R.D.W., R.L.); Kaufman Center for Heart Failure, Department of Thoracic and Cardiovascular Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio (C.S.M.); Bluhm Cardiovascular Institute, Feinberg School of Medicine, Division of Cardiothoracic Surgery, Northwestern University, Chicago, Ill (P.M.M.); and St Michael’s Hospital, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada (S.V.).
Reprint requests to Paul W.M. Fedak, MD, PhD, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, M5G 2C4, Canada. E-mail paul.fedak{at}utoronto.ca
Received June 24, 2005; revision received October 2, 2005; accepted October 28, 2005.
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.
Methods and 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 ß1D and ß3 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 ß1D cleavage ratio was elevated, indicating receptor shedding. ADAM10 and ADAM15 expressions correlated with the cleavage ratio. ADAM10 colocalized with integrin ß1D 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 ß1D expression. ADAM12 and integrin ß1D 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.
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