Temporally controlled onset of dilated cardiomyopathy through disruption of the SRF gene in adult heart.
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.


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 alpha-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.
Parlakian
Ara
A
Molecular Biology of Differentiation, The Université Paris 7, EA300, Paris, France.
Charvet
Claude
C
Escoubet
Brigitte
B
Mericskay
Mathias
M
Molkentin
Jeffery D
JD
Gary-Bobo
Guillaume
G
De Windt
Leon J
LJ
Ludosky
Marie-Aline
MA
Paulin
Denise
D
Daegelen
Dominique
D
Tuil
David
D
Li
Zhenlin
Z
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000196:embryology / Q000503:physiopathology*; D006720:Homozygote; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026362:Serum Response Factor / Q000172:deficiency* / Q000235:genetics*
D026362:Serum Response Factor