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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
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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.
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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