title: Temporally controlled onset of dilated cardiomyopathy through disruption of the SRF gene in adult heart.
abstract: 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.
authors.affiliation: Molecular Biology of Differentiation, The Université Paris 7, EA300, Paris, France.
authors.forename: Ara
authors.initials: A
authors.lastname: Parlakian
authors.forename: Claude
authors.initials: C
authors.lastname: Charvet
authors.forename: Brigitte
authors.initials: B
authors.lastname: Escoubet
authors.forename: Mathias
authors.initials: M
authors.lastname: Mericskay
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gary-Bobo
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
authors.forename: Marie-Aline
authors.initials: MA
authors.lastname: Ludosky
authors.forename: Denise
authors.initials: D
authors.lastname: Paulin
authors.forename: Dominique
authors.initials: D
authors.lastname: Daegelen
authors.forename: David
authors.initials: D
authors.lastname: Tuil
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Li
mesh_terms: 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*
chemical_list: D026362:Serum Response Factor