Activin-A, transforming growth factor-beta, and myostatin signaling pathway in experimental dilated cardiomyopathy.

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)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-TGFbeta-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. TGFbeta 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, follistatin-related 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 TGFbeta-activin-A/Smad signaling pathway and their target gene p21 and by the absence of ventricular hypertrophy.

• Authors: Maryam Mahmoudabady, Myrielle Mathieu, Laurence Dewachter, Ielham Hadad, Lynn Ray, Pascale Jespers, Serge Brimioulle, Robert Naeije, Kathleen McEntee
• Journal: Journal of cardiac failure (J Card Fail) Vol. 14 Issue 8 Pg. 703-9 (Oct 2008) ISSN: 1532-8414 [Electronic] United States
• PMID: 18926443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p21
• Cytokines
• Intercellular Signaling Peptides and Proteins
• Myostatin
• activin A
• Activins
• Cyclin D1

Topics

• Activins (metabolism)
• Animals
• Cardiomyopathy, Dilated (diagnostic imaging, genetics, metabolism)
• Cyclin D1 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cytokines (metabolism)
• Disease Progression
• Dogs
• Gene Expression
• Intercellular Signaling Peptides and Proteins (metabolism)
• Models, Animal
• Myostatin (metabolism)
• Signal Transduction
• Ultrasonography