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Rôles et mécanismes d’action de la protéine Epac dans l’hypertrophie cardiaque

Abstract : Catecholamines regulate cardiac function by stimulating β-adrenergic receptors (β-AR), leading to cAMP production and activation of a multiplicity of signaling pathways. Epac proteins are exchange factors for small G proteins which are directly activated by cAMP. Given the importance of the β-adrenergic pathway in cardiac physiopathology, it becomes essential to characterize functions of Epac protein in myocardium. In a first part, this study shows that H-Ras and Rap2B GTPases are involved in Epac-induced neonatal rat cardiac myocytes hypertrophy. Epac induces activation of the PLC/IP3/Ca2+ pathway which is necessary for H-Ras activation. At the transcriptional level, Epac causes HDAC4 nuclear export leading to activation of a hypertrophic gene program. In a second part, this study reveals implication of Epac1 in cardiac hypertrophy in vivo. Deletion of Epac1 in mice protects from cardiac remodeling induced by chronic isoproterenol infusion and enhances cardiac function. Cardiac specific overexpression of Epac1 in mice induces cardiac myocytes hypertrophy. Interestingly, β-AR/Epac1 pathway triggers ubiquitinated proteins accumulation and activation of autophagy both in vitro and in vivo. By eliminating aggregates and by counteracting hypertrophic effects of Epac, autophagy protects from deleterious effects of the β-AR/Epac pathway. These results open news insights into the treatment of cardiac hypertrophy and heart failure.
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https://theses.hal.science/tel-01188983
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Submitted on : Wednesday, September 2, 2015 - 10:27:11 AM
Last modification on : Friday, November 25, 2022 - 3:32:28 AM
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  • HAL Id : tel-01188983, version 2

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Anne-Coline Laurent. Rôles et mécanismes d’action de la protéine Epac dans l’hypertrophie cardiaque. Cardiologie et système cardiovasculaire. Université Paris Sud - Paris XI, 2013. Français. ⟨NNT : 2013PA11T044⟩. ⟨tel-01188983v2⟩

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