Published Online
on October 31, 2005

A more recent version of this article appeared on November 8, 2005

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Submitted on January 5, 2005
Revised on July 4, 2005
Accepted on July 18, 2005

Temporally Controlled Onset of Dilated Cardiomyopathy Through Disruption of the SRF Gene in Adult Heart

Ara Parlakian PhD, Claude Charvet MS, Brigitte Escoubet MD, PhD, Mathias Mericskay PhD, Jeffery D. Molkentin PhD, Guillaume Gary-Bobo MS, Leon J. De Windt PhD, Marie-Aline Ludosky MS, Denise Paulin PhD, Dominique Daegelen PhD, David Tuil PhD, and Zhenlin Li PhD^*

From the Université Paris 7, Molecular Biology of Differentiation, EA300, Paris, France (A.P., D.P.); Institut Cochin, Université René Descartes-Paris 5, INSERM U567, UMR CNRS 8104, Paris, France (C.C., D.D., D.T.); Faculté de Médecine Xavier-Bichat, Université Paris 7, Assistance Publique-Hôpitaux de Paris, INSERM U426, CEFI IFR02, Paris, France (B.E.); Department of Pediatrics, Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio (J.D.M.); Hubrecht Laboratory and Interuniversity Cardiology Institute, Utrecht, Netherlands (L.J. De W.); Institut Jacques Monod, UMR 7592, Paris, France (M.L.); and Université Pierre et Marie Curie, Physiology and Physiopathology, UMR 7079, Paris, France (M.M., G.G.-B., Z.L.).

^* To whom correspondence should be addressed. E-mail: zhenli{at}ccr.jussieu.fr.

Background--Serum response factor (SRF) is a cardiac transcription factor involved in cell growth and differentiation. We have shown, using the Cre/loxP system, that cardiac-specific disruption of SRF gene in the embryonic heart results in lethal cardiac defects. The role of SRF in adult heart is unknown.

Methods and Results--We disrupted SRF in the adult heart using a heart-specific tamoxifen-inducible Cre recombinase. This disruption led to impaired left ventricular function with reduced contractility, subsequently progressing to dilated cardiomyopathy, as demonstrated by serial echocardiography, including tissue Doppler imaging. The cytoarchitecture of cardiomyocytes was altered in the intercalated disks. All mutant mice died from heart failure 10 weeks after treatment. These functional and structural defects were preceded by early alterations in the cardiac gene expression program: major decreases in mRNA levels for cardiac -actin, muscle creatine kinase, and calcium-handling genes.

Conclusions--SRF is crucial for adult cardiac function and integrity. We suggest that the rapid progression to heart failure in SRF mutant mice results primarily from decreased expression of proteins involved in force generation and transmission, low levels of polymerized actin, and changes in cytoarchitecture, without hypertrophic compensation. These cardiac-specific SRF-deficient mice have the morphological and clinical features of acquired dilated cardiomyopathy in humans and may therefore be used as an inducible model of this disorder.

Key words: cardiomyopathy • contractility • echocardiography • genes • heart failure • molecular biology • myocardium

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