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Identification of Epac1 transcriptomic signature in ventricular myocytes
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Edité par CCSD -
International audience. IntroductionExchange protein directly activated by cAMP 1 (Epac1) is a direct effector of cyclic adenosine monophosphate (cAMP) and has been shown to play multiple roles in cardiovascular diseases progression. We recently identified AM-001 (thieno[2,3- b]pyridine derivative) as a selective non-competitive antagonist of Epac1 that reduced cardiac pathological remodeling induced by chronic β-adrenergic stimulation. AM-001, therefore, rises as a powerful pharmacological tool to investigate Epac1-dependent pathophysiological processes.ObjectiveThe aim of this study was to assess the impact of Epac1 pharmacological modulation on gene expression in neonatal rat ventricular myocytes (NRVMs) to further characterize the role of Epac1 signalosome in cardiac disease progression.MethodsNRVMs transfected with Epac1 were treated or not for 6h with a specific Epac1 agonist, 8CPT-AM (8-(4-Chlorophenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate, acetoxymethyl ester; 10 μM) and/or AM-001 (20 μM). Following RNA extraction, RNA-seq was performed with a Nextseq (paired-end reads; < 2x30 M reads per sample).ResultsPathway enrichment analysis performed with topGO package revealed that Epac1 pharmacological modulation (8-CPT-AM vs AM-001) regulated key gene ontology (GO) terms. Indeed, we found that Epac1 significantly impacted the expression of genes involved in mitochondrial respiratory chain and, lipid and glucose metabolism. This is consistent with the cardiomyocyte subcellular localization of Epac1 in mitochondria. As expected, Epac1 influenced the expression of genes implicated in cardiomyocyte remodeling. Interestingly, we identified a whole set of Epac1 target genes regulating the biosynthesis of cholesterol.ConclusionOur work describes for the first time the transcriptome of Epac1 in cardiomyocytes. This analysis provides us clues to better understand the mechanism underlying the pathological processes induced by Epac1 and, thus, to identify potential new therapeutic targets for cardiac diseases.
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