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Journal of Cardiac Failure Volume 14, Issue 8, October 2008, Pages 703-709 Activin-A, Transforming Growth Factor-β, and Myostatin Signaling Pathway in Experimental Dilated Cardiomyopathy Mahmoudabady, M.ab, Mathieu, M.a, Dewachter, L.a, Hadad, I.a, Ray, L.a, Jespers, P.a, Brimioulle, S.a, Naeije, R.a, McEntee, K.a a Laboratory of Physiology, Université Libre de Bruxelles, Brussels, Belgium b Department of Physiology, Ghaem Hospital, Mashad University of Medical Sciences, Mashad, Iran View references (33) Abstract Background: The pathogenic mechanisms of dilated cardiomyopathy are still uncertain. A number of cytokines and growth factors participate in the remodeling process of the disease. Methods: We investigated the cardiac myostatin, transforming growth factor (TGF)β, and activin-A/Smad growth inhibitory signaling pathway in experimental dilated cardiomyopathy. Transvenous endomyocardial biopsies of the interventricular septum were taken weekly in 15 beagle dogs during the development of heart failure (HF) induced by rapid pacing over a period of 7 weeks. Genes involved in the myostatin-TGFβ-activin-A/Smad signaling pathway and the cardiac hypertrophic process were quantified by real-time quantitative polymerase chain reaction. Left ventricular volume, function, and mass were evaluated by echocardiography. Results: Overpacing was associated with increased left ventricular volumes and decreased ejection fraction, whereas the left ventricular mass remained unchanged. TGFβ was increased in moderate HF. Activin-A mRNA expression was 4-fold higher in overt congestive HF than at baseline. A 2-fold decrease of activin type II receptors and activin receptor interacting protein 2 gene expressions were observed, as well as a transient decrease of follistatin. Activin type I receptors, activin receptor interacting protein 1, follistatinrelated gene, and myostatin remained unchanged. The inhibitory Smad 7, a negative feedback loop regulator of the Smad pathway, was overexpressed in severe HF. Gene expression of the cyclin-dependent kinase inhibitor p21, a direct target gene of the Smad pathway, was 8-fold up-regulated in HF, whereas cyclin D1 was down-regulated. Conclusion: We conclude that tachycardia-induced dilated cardiomyopathy is characterized by gene overexpression of the TGFβ-activin-A/Smad signaling pathway and their target gene p21 and by the absence of ventricular hypertrophy. © 2008 Elsevier Inc. All rights reserved. Reaxys Database Information | Author keywords Cell cycle; cytokine; heart failure; hypertrophy; p21; TGFβ Indexed Keywords EMTREE drug terms: activin A; activin receptor 1; cyclin dependent kinase inhibitor 1A; follistatin; messenger RNA; myostatin; Smad7 protein; transforming growth factor beta EMTREE medical terms: animal experiment; animal model; article; congestive cardiomyopathy; congestive heart failure; controlled study; echocardiography; gene overexpression; heart left ventricle function; heart left ventricle mass; heart left ventricle volume; heart muscle biopsy; heart ventricle hypertrophy; heart ventricle septum; male; nonhuman; priority journal; real time polymerase chain reaction; tachycardia MeSH: Activins; Animals; Cardiomyopathy, Dilated; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cytokines; Disease Progression; Dogs; Gene Expression; Intercellular Signaling Peptides and Proteins; Models, Animal; Myostatin; Signal Transduction Medline is the source for the MeSH terms of this document. Chemicals and CAS Registry Numbers: activin A, 104625-48-1; follistatin, 117628-82-7; myostatin, 197731-05-8; Smad7 protein, 391971-60-1;activin A; Activins, 104625-48-1; Cyclin D1, 136601-57-5; Cyclin-Dependent Kinase Inhibitor p21; Cytokines; Intercellular Signaling Peptides and Proteins; Myostatin ISSN: 10719164 CODEN: JCFAFSource Type: Journal Original language: English DOI: 10.1016/j.cardfail.2008.05.003 PubMed ID: 18926443Document Type: Article