title: AMPK activation by glucagon-like peptide-1 prevents NADPH oxidase activation induced by hyperglycemia in adult cardiomyocytes.
abstract: Exposure of cardiomyocytes to high glucose concentrations (HG) stimulates reactive oxygen species (ROS) production by NADPH oxidase (NOX2). NOX2 activation is triggered by enhanced glucose transport through a sodium-glucose cotransporter (SGLT) but not by a stimulation of glucose metabolism. The aim of this work was to identify potential therapeutic approaches to counteract this glucotoxicity. In cultured adult rat cardiomyocytes incubated with 21 mM glucose (HG), AMP-activated protein kinase (AMPK) activation by A769662 or phenformin nearly suppressed ROS production. Interestingly, glucagon-like peptide 1 (GLP-1), a new antidiabetic drug, concomitantly induced AMPK activation and prevented the HG-mediated ROS production (maximal effect at 100 nM). α2-AMPK, the major isoform expressed in cardiomyocytes (but not α1-AMPK), was activated in response to GLP-1. Anti-ROS properties of AMPK activators were not related to changes in glucose uptake or glycolysis. Using in situ proximity ligation assay, we demonstrated that AMPK activation prevented the HG-induced p47phox translocation to caveolae, whatever the AMPK activators used. NOX2 activation by either α-methyl-d-glucopyranoside, a glucose analog transported through SGLT, or angiotensin II was also counteracted by GLP-1. The crucial role of AMPK in limiting HG-mediated NOX2 activation was demonstrated by overexpressing a constitutively active form of α2-AMPK using adenoviral infection. This overexpression prevented NOX2 activation in response to HG, whereas GLP-1 lost its protective action in α2-AMPK-deficient mouse cardiomyocytes. Under HG, the GLP-1/AMPK pathway inhibited PKC-β2 phosphorylation, a key element mediating p47phox translocation. In conclusion, GLP-1 induces α2-AMPK activation and blocks HG-induced p47phox translocation to the plasma membrane, thereby preventing glucotoxicity.
authors.affiliation: Pôles de Recherche Cardiovasculaire.
authors.forename: Magali
authors.initials: M
authors.lastname: Balteau
authors.affiliation: Pôles de Recherche Cardiovasculaire.
authors.forename: Anne
authors.initials: A
authors.lastname: Van Steenbergen
authors.affiliation: Pôles de Recherche Cardiovasculaire.
authors.forename: Aurélie D
authors.initials: AD
authors.lastname: Timmermans
authors.affiliation: Pharmacothérapie et Thérapeutique.
authors.forename: Chantal
authors.initials: C
authors.lastname: Dessy
authors.affiliation: Pharmacothérapie et Thérapeutique.
authors.forename: Gaetane
authors.initials: G
authors.lastname: Behets-Wydemans
authors.affiliation: Institute of Neuroscience, Division of Cell Physiology, and.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tajeddine
authors.affiliation: Pôles de Recherche Cardiovasculaire.
authors.forename: Diego
authors.initials: D
authors.lastname: Castanares-Zapatero
authors.affiliation: Endocrinologie, Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique (IREC), and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Gilon
authors.affiliation: Pôles de Recherche Cardiovasculaire, Cliniques universitaires Saint Luc, Division of Cardiology, Brussels, Belgium.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vanoverschelde
authors.affiliation: Pôles de Recherche Cardiovasculaire.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Horman
authors.affiliation: de Duve Institute, Université catholique de Louvain (UCL), Brussels;
authors.forename: Louis
authors.initials: L
authors.lastname: Hue
authors.affiliation: Pôles de Recherche Cardiovasculaire.
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
authors.affiliation: Pôles de Recherche Cardiovasculaire, Cliniques universitaires Saint Luc, Division of Cardiology, Brussels, Belgium christophe.beauloye@uclouvain.be.
authors.forename: Christophe
authors.initials: C
authors.lastname: Beauloye
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008757:Methylglucosides / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D010629:Phenformin / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D011753:Pyrones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D001713:Biphenyl Compounds; D007004:Hypoglycemic Agents; D008562:Membrane Glycoproteins; D008757:Methylglucosides; D011753:Pyrones; D017382:Reactive Oxygen Species; D013876:Thiophenes; C027020:methylglucoside; D052216:Glucagon-Like Peptide 1; D010629:Phenformin; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
keywords: AMP-activated protein kinase; glucagon-like peptide-1; glucose; heart; oxidative stress