title: Exchange protein directly activated by cAMP 1 promotes autophagy during cardiomyocyte hypertrophy.
abstract: OBJECTIVE
  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 how altered autophagy has an impact on Epac1-induced cardiomyocyte hypertrophy.
  
  
  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 β-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 Ca(2+)/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.
  
  
  CONCLUSIONS
  Altogether, these findings demonstrate that autophagy is an adaptive response to antagonize Epac1-promoted cardiomyocyte hypertrophy.
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse F-31432, France Université de Toulouse, UPS, Toulouse F-31432, France.
authors.forename: Anne-Coline
authors.initials: AC
authors.lastname: Laurent
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse F-31432, France Université de Toulouse, UPS, Toulouse F-31432, France.
authors.forename: Malik
authors.initials: M
authors.lastname: Bisserier
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse F-31432, France Université de Toulouse, UPS, Toulouse F-31432, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Lucas
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse F-31432, France Université de Toulouse, UPS, Toulouse F-31432, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Tortosa
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse F-31432, France Université de Toulouse, UPS, Toulouse F-31432, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Roumieux
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse F-31432, France Université de Toulouse, UPS, Toulouse F-31432, France.
authors.forename: Annélie
authors.initials: A
authors.lastname: De Régibus
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse F-31432, France Université de Toulouse, UPS, Toulouse F-31432, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Swiader
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse F-31432, France Université de Toulouse, UPS, Toulouse F-31432, France.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Sainte-Marie
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse F-31432, France Université de Toulouse, UPS, Toulouse F-31432, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Heymes
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse F-31432, France Université de Toulouse, UPS, Toulouse F-31432, France cecile.vindis@inserm.fr frank.lezoualch@inserm.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Vindis
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse F-31432, France Université de Toulouse, UPS, Toulouse F-31432, France cecile.vindis@inserm.fr frank.lezoualch@inserm.fr.
authors.forename: Frank
authors.initials: F
authors.lastname: Lezoualc'h
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D049108:Cell Enlargement; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: C588037:6-fluoro-5,7-dibromo-2-methyl-1-formyl-1,2,3,4-tetrahydroquinoline; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D011804:Quinolines; C526973:Rapgef3 protein, rat; D011943:Receptors, Adrenergic, beta; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP
keywords: Autophagy; Cardiac hypertrophy; Epac1; β-Adrenergic receptor