title: A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake.
abstract: AMP-activated protein kinase (AMPK), a key cellular sensor of energy, regulates metabolic homeostasis and plays a protective role in the ischemic or diabetic heart. Stimulation of cardiac glucose uptake contributes to this AMPK-mediated protection. The small-molecule AMPK activator A-769662, which binds and directly activates AMPK, has recently been characterized. A-769662-dependent AMPK activation protects the heart against an ischemia-reperfusion episode but is unable to stimulate skeletal muscle glucose uptake. Here, we tried to reconcile these conflicting findings by investigating the impact of A-769662 on cardiac AMPK signaling and glucose uptake. We showed that A-769662 promoted AMPK activation, resulting in the phosphorylation of several downstream targets, but was incapable of stimulating glucose uptake in cultured cardiomyocytes and the perfused heart. The lack of glucose uptake stimulation can be explained by A-769662's narrow specificity, since it selectively activates cardiac AMPK heterotrimeric complexes containing α2/β1-subunits, the others being presumably required for this metabolic outcome. However, when combined with classical AMPK activators, such as metformin, phenformin, oligomycin, or hypoxia, which impact AMPK heterotrimers more broadly via elevation of cellular AMP levels, A-769662 induced more profound AMPK phosphorylation and subsequent glucose uptake stimulation. The synergistic effect of A-769662 under such ischemia-mimetic conditions protected cardiomyocytes against ROS production and cell death. In conclusion, despite the fact that A-769662 activates AMPK, it alone does not significantly stimulate glucose uptake. However, strikingly, its ability of potentiating the action on other AMPK activators makes it a potentially useful participant in the protective role of AMPK in the heart.
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium;
authors.forename: Aurélie D
authors.initials: AD
authors.lastname: Timmermans
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium;
authors.forename: Magali
authors.initials: M
authors.lastname: Balteau
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium;
authors.forename: Roselle
authors.initials: R
authors.lastname: Gélinas
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium;
authors.forename: Edith
authors.initials: E
authors.lastname: Renguet
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium;
authors.forename: Audrey
authors.initials: A
authors.lastname: Ginion
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium;
authors.forename: Carole
authors.initials: C
authors.lastname: de Meester
authors.affiliation: Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom;
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pole of Pharmacology and Therapeutics, Brussels, Belgium; and.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Balligand
authors.affiliation: Université catholique de Louvain, de Duve Institute, Brussels, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bontemps
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium;
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vanoverschelde
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium;
authors.forename: Sandrine
authors.initials: S
authors.lastname: Horman
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium;
authors.forename: Christophe
authors.initials: C
authors.lastname: Beauloye
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium; luc.bertrand@uclouvain.be.
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010629:Phenformin / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D007328:Insulin; D011753:Pyrones; D017382:Reactive Oxygen Species; D013876:Thiophenes; D000249:Adenosine Monophosphate; D010629:Phenformin; 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: A-769662; AMP-activated protein kinase; cardiomyocytes; glucose uptake; perfused hearts