Résumé :
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Serum response factor (SRF) is a transcription factor controlling the expression of many extracellular signal-regulated genes as well as genes encoding sarcomeric contractile proteins. Many SRF target genes are involved in familial hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). By using the tamoxifen inducible Cre/loxP system, we have previously shown that SRF is crucial for adult cardiac function and integrity. Triggering in mice cardiac-restricted knock out of SRF led to impaired left ventricular function with reduced contractility, subsequently progressing to DCM without hypertrophic compensation. Under these conditions, all mutant mice died from heart failure 10 weeks after tamoxifen injections. Functional and structural heart defects were preceded by early alterations in the cardiac gene expression program particularly for cardiac ?-actin, IGF-1, muscle creatine kinase and calcium-handling genes. To evaluate the importance of altered IGF-1 and cardiac ?-actin genes expression in the progression of DCM and compensate for their loss, we mated our mice model of inducible SRF disruption with transgenic mice overexpressing either IGF-1 or cardiac ?-actin specifically in the heart. Cardiac-specific IGF-1 or cardiac ?-actin overexpression both attenuates the progression of DCM due to the loss of SRF. Cardiac IGF-1 overexpression improves functional parameters and the survival of the animals until almost 4 months. In the same way, an almost normal cardiac function and a life extension beyond 6 months were associated to cardiac ?-actin compensatory expression. Histological and molecular analysis of these new models are in progress.
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