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

Anne Coline Laurent, Malik Bisserier, Alexandre Lucas, Florence Tortosa, Marie Roumieux, Annélie De Régibus, Audrey Swiader, Yannis Sainte-Marie, Christophe Heymes, Cécile Vindis, Frank Lezoualc'h

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


Aims Stimulation of β-adrenergic receptors (β-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 howaltered 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 b-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 β-AR-induced cardiac remodelling and prevented the induction of autophagy. The signalling mechanisms underlying Epac1-induced autophagy involved a Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ)/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.

Original languageEnglish
Pages (from-to)55-64
Number of pages10
JournalCardiovascular Research
Issue number1
StatePublished - 1 Jan 2015
Externally publishedYes


  • Autophagy
  • Cardiac hypertrophy
  • Epac1
  • β-Adrenergic receptor


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