title: Epac is required for GLP-1R-mediated inhibition of oxidative stress and apoptosis in cardiomyocytes.
abstract: Although the cardioprotective effects of glucagon-like peptide-1 and its analogs have been reported, the exact mechanisms of the glucagon-like peptide-1 receptor (GLP-1R) signaling pathway in the heart are still unclear. Activation of the GLP-1R has been shown to increase cAMP levels, thus eliciting protein kinase A- and exchange protein activated by cAMP (Epac)-dependent signaling pathways in pancreatic β-cells. However, which pathway plays an important role in the antioxidant and antiapoptotic effects of GLP-1R activation in the heart is not known. In this study, we demonstrated that stimulation of GLP-1Rs with exendin-4 attenuated H2O2-induced reactive oxygen species production and increased the synthesis of antioxidant enzymes, catalase, glutathione peroxidase-1, and manganese superoxide dismutase that is dependent on Epac. Additionally, exendin-4 has an antiapoptotic effect by decreasing a number of apoptotic cells, inhibiting caspase-3 activity, and enhancing the expression of antiapoptotic protein B-cell lymphoma 2, which is mediated through both protein kinase A- and Epac-dependent pathways. These data indicate a critical role for Epac in GLP-1R-mediated cardioprotection.
authors.affiliation: Department of Pharmacology (S.M., P.H., W.P.), Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand; and Cardiac Electrophysiology Research and Training Center (N.C.), Faculty of Medicine, and Excellence Center in Cardiac Electrophysiology (N.C.), Department of Physiology, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Supachoke
authors.initials: S
authors.lastname: Mangmool
authors.forename: Piriya
authors.initials: P
authors.lastname: Hemplueksa
authors.forename: Warisara
authors.initials: W
authors.lastname: Parichatikanond
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D020662:Guanine Nucleotide Exchange Factors; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C526973:Rapgef3 protein, rat; D017382:Reactive Oxygen Species; D014688:Venoms; D000077270:Exenatide; D006861:Hydrogen Peroxide; D053148:Caspase 3