Mosaic inactivation of the serum response factor gene in the myocardium induces focal lesions and heart failure.
OBJECTIVE
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 alpha-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.
Gary-Bobo
Guillaume
G
UPMC Univ Paris 06, UMR7079, physiology and Physiopathology, Paris, France.
Parlakian
Ara
A
Escoubet
Brigitte
B
Franco
Claudio Areias
CA
Clément
Sophie
S
Bruneval
Patrick
P
Tuil
David
D
Daegelen
Dominique
D
Paulin
Denise
D
Li
Zhenlin
Z
Mericskay
Mathias
M
D000483:Alleles; D000704:Analysis of Variance; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D009030:Mosaicism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026362:Serum Response Factor / Q000172:deficiency / Q000235:genetics*
D026362:Serum Response Factor