© 2008 European Society of Cardiology
Mosaic inactivation of the serum response factor gene in the myocardium induces focal lesions and heart failure
a UPMC Univ Paris 06, UMR7079, physiology and Physiopathology Paris, France
b CNRS, UMR 7079 Paris, France
c Denis Diderot University Paris 7, CEFI IFR02 Faculté de Médecine Xavier-Bichat Paris, France
d Assistance Publique-Hôpitaux de Paris, Bichat Hospital Paris, France
e INSERM, U722 Paris, France
f University of Geneva, Department of Clinical Pathology Geneva, Switzerland
g Assistance Publique-Hôpitaux de Paris, George Pompidou European Hospital Paris, France
h René Descartes University, Cochin Institute, INSERM U567 and CNRS UMR 8104, Genetics and development department Paris, France
* Corresponding author. UPMC Univ Paris 06, CNRS UMR7079, physiology and Physiopathology, BP256, 7 Quai St-Bernard, 75005 Paris, France. Tel.: +33 1 44 27 21 36; fax: 33 1 44 27 21 35. E-mail address: zhenli{at}ccr.jussieu.fr (Z. Li).
 |
Abstract |
|---|
Background and aims: Regional alterations in ventricular mechanical functions are a primary determinant for the risk of myocardial injuries in various cardiomyopathies. The serum response factor (SRF) is a transcription factor regulating contractile and cytoskeletal genes and may play an important role in the remodelling of myocardium at the cellular level.
Methods: Using Desmin-Cre transgenic mice, we generated a model of mosaic inactivation of a floxed-Srf allele in the heart to analyze the consequence of regional alterations of SRF-mediated functions in the myocardium.
Results: Two types of cardiomyocytes co-existed in the Desmin-Cre:Sf/Sf mice. Cardiomyocytes lacking SRF became thin and elongated while cardiomyocytes containing SRF became hypertrophic. Several physiological contractile genes were down-regulated while skeletal 
-actin was induced in SRF positive area only. Mutants developed heart failure associated with the presence of focal lesions in the myocardium, and died before month 11.
Conclusions: Juxtaposition of functional SRF wild-type and failing SRF mutant cardiomyocytes generates deleterious heterogeneity in the myocardium. Our results show that SRF contributes to the capacity of cardiomyocytes to remodel their shape and contractile functions in response to their local environment; suggesting that it may play a role in pathologies involving regional alterations of ventricular mechanics in the heart.
Key Words: Myocardial injury • Regional ventricular dysfunction • Mosaic Cre recombination • Actin • Eccentric and concentric hypertrophy
Received January 11, 2008; Revised April 3, 2008; Accepted April 24, 2008