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: Aurélie D Timmermans, Magali Balteau, Roselle Gélinas, Edith Renguet, Audrey Ginion, Carole de Meester, Kei Sakamoto, Jean-Luc Balligand, Françoise Bontemps, Jean-Louis Vanoverschelde, Sandrine Horman, Christophe Beauloye, Luc Bertrand
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 306 Issue 12 Pg. H1619-30 (Jun 15 2014) ISSN: 1522-1539 [Electronic] United States
• PMID: 24748590 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the American Physiological Society.

Chemical References

• Biphenyl Compounds
• Insulin
• Pyrones
• Reactive Oxygen Species
• Thiophenes
• Adenosine Monophosphate
• Phenformin
• AMP-Activated Protein Kinases
• Glucose
• 4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile

Topics

• AMP-Activated Protein Kinases (drug effects, metabolism)
• Adenosine Monophosphate (metabolism)
• Animals
• Biphenyl Compounds
• Cells, Cultured
• Glucose (metabolism)
• Insulin (pharmacology)
• Male
• Models, Animal
• Myocardial Reperfusion Injury (metabolism, prevention & control)
• Myocardium (metabolism)
• Myocytes, Cardiac (drug effects, metabolism)
• Phenformin (pharmacology)
• Pyrones (pharmacology)
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Thiophenes (pharmacology)