4.5 Article

Activin-A, Transforming Growth Factor-β, and Myostatin Signaling Pathway in Experimental Dilated Cardiomyopathy

Journal

JOURNAL OF CARDIAC FAILURE
Volume 14, Issue 8, Pages 703-709

Publisher

CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS
DOI: 10.1016/j.cardfail.2008.05.003

Keywords

Cell cycle; cytokine; heart failure; hypertrophy; p21; TGF beta

Funding

  1. Foundation for Cardiac Surgery, Belgium
  2. Ministry of Health and Medical Education, Iran

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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)beta, 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-TGF beta-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. TGF was increased in moderate HE 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 I, follistatin-related gene, and myostatin remained unchanged. The inhibitory Smad 7, a negative feedback loop regulator of the Smad pathway, was overexpressed in severe HE 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 TGF beta-activin-A/Smad signaling pathway and their target gene p21 and by the absence of ventricular hypertrophy. (J Cardiac Fail 2008;14:703-709)

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