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Exchange protein directly activated by cAMP 1 promotes autophagy during cardiomyocyte hypertrophy.

Authors: Laurent, AC  Bisserier, M  Lucas, A  Tortosa, F  Roumieux, M  De Regibus, A  Swiader, A  Sainte-Marie, Y  Heymes, C  Vindis, C  Lezoualc'h, F 
Citation: Laurent AC, etal., Cardiovasc Res. 2015 Jan 1;105(1):55-64. doi: 10.1093/cvr/cvu242. Epub 2014 Nov 19.
Pubmed: (View Article at PubMed) PMID:25411381
DOI: Full-text: DOI:10.1093/cvr/cvu242

AIMS: Stimulation of beta-adrenergic receptors (beta-AR) increases cAMP production and contributes to the pathogenesis of cardiac hypertrophy and failure through poorly understood mechanisms. We previously demonstrated that Exchange protein directly activated by cAMP 1 (Epac1)-induced hypertrophy in primary cardiomyocytes. Among the mechanisms triggered by cardiac stress, autophagy has been highlighted as a protective or harmful response. Here, we investigate whether Epac1 promotes cardiac autophagy and how altered autophagy has an impact on Epac1-induced cardiomyocyte hypertrophy. METHODS AND RESULTS: We reported that direct stimulation of Epac1 with the agonist, Sp-8-(4-chlorophenylthio)-2'-O-methyl-cAMP (Sp-8-pCPT) promoted autophagy activation in neonatal cardiomyocytes. Stimulation of beta-AR with isoprenaline (ISO) mimicked the effect of Epac1 on autophagy markers. Conversely, the induction of autophagy flux following ISO treatment was prevented in cardiomyocytes pre-treated with a selective inhibitor of Epac1, CE3F4. Importantly, we found that Epac1 deletion in mice protected against beta-AR-induced cardiac remodelling and prevented the induction of autophagy. The signalling mechanisms underlying Epac1-induced autophagy involved a Ca(2+)/calmodulin-dependent kinase kinase beta (CaMKKbeta)/AMP-dependent protein kinase (AMPK) pathway. Finally, we provided evidence that pharmacological inhibition of autophagy using 3-methyladenine (3-MA) or down-regulation of autophagy-related protein 5 (Atg5) significantly potentiated Epac1-promoted cardiomyocyte hypertrophy. CONCLUSION: Altogether, these findings demonstrate that autophagy is an adaptive response to antagonize Epac1-promoted cardiomyocyte hypertrophy.

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CRRD Object Information
CRRD ID: 9850089
Created: 2015-03-26
Species: All species
Last Modified: 2015-03-26
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.