A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake
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A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake. / Timmermans, Aurélie D.; Balteau, Magali; Gélinas, Roselle; Renguet, Edith; Ginion, Audrey; de Meester, Carole; Sakamoto, Kei; Balligand, Jean Luc; Bontemps, Françoise; Vanoverschelde, Jean Louis; Horman, Sandrine; Beauloye, Christophe; Bertrand, Luc.
I: American Journal of Physiology - Heart and Circulatory Physiology, Bind 306, Nr. 12, 15.06.2014, s. H1619-H1630.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake
AU - Timmermans, Aurélie D.
AU - Balteau, Magali
AU - Gélinas, Roselle
AU - Renguet, Edith
AU - Ginion, Audrey
AU - de Meester, Carole
AU - Sakamoto, Kei
AU - Balligand, Jean Luc
AU - Bontemps, Françoise
AU - Vanoverschelde, Jean Louis
AU - Horman, Sandrine
AU - Beauloye, Christophe
AU - Bertrand, Luc
PY - 2014/6/15
Y1 - 2014/6/15
N2 - 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.
AB - 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.
KW - A-769662
KW - AMP-activated protein kinase
KW - Cardiomyocytes
KW - Glucose uptake
KW - Perfused hearts
UR - http://www.scopus.com/inward/record.url?scp=84901332717&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00965.2013
DO - 10.1152/ajpheart.00965.2013
M3 - Journal article
C2 - 24748590
AN - SCOPUS:84901332717
VL - 306
SP - H1619-H1630
JO - A J P: Heart and Circulatory Physiology (Online)
JF - A J P: Heart and Circulatory Physiology (Online)
SN - 1522-1539
IS - 12
ER -
ID: 239215437