Temporally controlled onset of dilated cardiomyopathy through disruption of the SRF gene in adult heart.
Circulation
; 112(19): 2930-9, 2005 Nov 08.
Article
em En
| MEDLINE
| ID: mdl-16260633
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. METHODS ANDRESULTS:
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.
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Base de dados:
MEDLINE
Assunto principal:
Cardiomiopatia Dilatada
/
Fator de Resposta Sérica
/
Coração
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
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Male
Idioma:
En
Revista:
Circulation
Ano de publicação:
2005
Tipo de documento:
Article
País de afiliação:
França