Preconditioning Enhanced Glucose Uptake Is Mediated by p38 MAP Kinase Not by Phosphatidylinositol 3-Kinase

Tong, Haiyan; Chen, Weina; London, Robert E.; Murphy, Elizabeth; Steenbergen, Charles

doi:10.1074/jbc.275.16.11981

Cited by 80 publications

(53 citation statements)

References 50 publications

(60 reference statements)

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“…In addition, AMPK may activate downstream pathways that have cardioprotective roles during ischemiareperfusion. Indeed, AMPK has been shown to activate p38-MAPK in the cardiac myocyte, which may also contribute to increased glucose uptake (80,104,127). These observations are consistent with an AMPK-mediated increase in glucose utilization being beneficial during and following ischemia.…”

Section: Regulation Of Myocardial Energy Utilizationsupporting

confidence: 75%

Role of AMP-activated protein kinase in healthy and diseased hearts

Dolinsky¹,

Dyck²

2006

American Journal of Physiology-Heart and Circulatory Physiology

118

105

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Dolinsky, Vernon W., and Jason R. B. Dyck. Role of AMP-activated protein kinase in healthy and diseased hearts. Am J Physiol Heart Circ Physiol 291: H2557-H2569, 2006. First published July 14, 2006 doi:10.1152/ajpheart.00329.2006.-The heart is capable of utilizing a variety of substrates to produce the necessary ATP for cardiac function. AMP-activated protein kinase (AMPK) has emerged as a key regulator of cellular energy homeostasis and coordinates multiple catabolic and anabolic pathways in the heart. During times of acute metabolic stresses, cardiac AMPK activation seems to be primarily involved in increasing energy-generating pathways to maintain or restore intracellular ATP levels. In acute situations such as mild ischemia or short durations of severe ischemia, activation of cardiac AMPK appears to be necessary for cardiac myocyte function and survival by stimulating ATP generation via increased glycolysis and accelerated fatty acid oxidation. Whereas AMPK activation may be essential for adaptation of cardiac energy metabolism to acute and/or minor metabolic stresses, it is unknown whether AMPK activation becomes maladaptive in certain chronic disease states and/or extreme energetic stresses. However, alterations in cardiac AMPK activity are associated with a number of cardiovascular-related diseases such as pathological cardiac hypertrophy, myocardial ischemia, glycogen storage cardiomyopathy, and Wolff-Parkinson-White syndrome, suggesting the possibility of a maladaptive role. Although the precise role AMPK plays in the diseased heart is still in question, it is clear that AMPK is a major regulator of cardiac energy metabolism. The consequences of alterations in AMPK activity and subsequent cardiac energy metabolism in the healthy and the diseased heart will be discussed. ischemia; cardiac hypertrophy; cardiac energy metabolism; glycogen THE HEART is capable of utilizing a variety of substrates to meet its immense demand for energy. Under normal physiological circumstances, cardiac function is dependent on the production of intracellular ATP derived primarily by the utilization of fatty acids, glucose, and lactate (123). A variety of transport proteins and regulatory enzymes control the uptake and subsequent metabolism of these energy substrates. Whereas many of these enzymes are regulated through substrate supply and/or energy demand, covalent modification of a number of these enzymes is also important. These regulatory mechanisms mediate substrate utilization and are essential for proper cardiac function.Fatty acids provide a concentrated supply of energy accounting for ϳ50 -75% of the myocardial acetyl CoA-derived ATP (84). Upon entering the cardiac myocyte, fatty acids are transported into the mitochondria and undergo ␤-oxidation to produce acetyl CoA that is eventually used to produce ATP. Glucose is transported into the cell via glucose transporters (GLUT) and can undergo glycolytic metabolism to generate pyruvate and ATP. This can occur in the absence of oxygen while still producing ATP. However, i...

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Section: Regulation Of Myocardial Energy Utilizationsupporting

confidence: 75%

Role of AMP-activated protein kinase in healthy and diseased hearts

Dolinsky¹,

Dyck²

2006

American Journal of Physiology-Heart and Circulatory Physiology

118

105

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“…In our study, the normalization of myocardial GLUT4 protein expression after rosiglitazone treatment was accompanied by normalization of glucose uptake during insulin stimulation or ischemia, suggesting a direct link between decreased GLUT4 protein expression and decreased glucose uptake. In support of this argument, different signaling pathways are involved in ischemia-and insulin-stimulated translocation of GLUT4 to the sarcolemma (37,38). Insulinstimulated glucose uptake requires phosphatidylinositol 3-kinase activation (39,40), whereas ischemia-induced GLUT4 translocation may involve AMP kinase and/or p38 MAP kinase activation (38,41).…”

Section: Coronary Flowmentioning

confidence: 95%

Thiazolidinedione Treatment Normalizes Insulin Resistance and Ischemic Injury in the Zucker Fatty Rat Heart

Sidell

Cole²,

Draper³

et al. 2002

Diabetes

149

128

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Obesity is associated with risk factors for cardiovascular disease, including insulin resistance, and can lead to cardiac hypertrophy and congestive heart failure. Here, we used the insulin-sensitizing agent rosiglitazone to investigate the cellular mechanisms linking insulin resistance in the obese Zucker rat heart with increased susceptibility to ischemic injury. Rats were treated for 7 or 14 days with 3 mg/kg per os rosiglitazone. Hearts were isolated and perfused before and during insulin stimulation or during 32 min low-flow ischemia at 0.3 ml ⅐ min ؊1 ⅐ grams wet wt ؊1 and reperfusion. D[2-3 H]glucose was used as a tracer of glucose uptake, and phosphorus-31 nuclear magnetic resonance spectroscopy was used to follow energetics during ischemia. At 12 months of age, obese rat hearts were insulin resistant with decreased GLUT4 protein expression. During ischemia, glucose uptake was lower and depletion of ATP was greater in obese rat hearts, thereby significantly impairing recovery of contractile function during reperfusion. Rosiglitazone treatment normalized the insulin resistance and restored GLUT4 protein levels in obese rat hearts. Glucose uptake during ischemia was also normalized by rosiglitazone treatment, thereby preventing the greater loss of ATP and restoring recovery of contractile function to that of lean rat hearts. We conclude that rosiglitazone treatment, by normalizing glucose uptake, protected obese rat hearts from ischemic injury.

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“…Myocardial glucose uptake is stimulated by metabolic stresses, including hypoxia and ischemia, by insulin-independent mechanisms (36). AMPK and p38 MAPK also regulate glucose uptake in response to metabolic stresses (12,28,36), possibly by distinct mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…AMPK and p38 MAPK also regulate glucose uptake in response to metabolic stresses (12,28,36), possibly by distinct mechanisms. Whereas AMPK stimulates glucose uptake by increasing the translocation of GLUT4 transporters to the cell surface (12,16,25,28), p38 MAPK may stimulate glucose uptake by increasing the intrinsic activity of GLUT4 transporters already at the cell surface (18,21,33).…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports suggest that p38 mitogen-activated protein kinase (MAPK), another stress-responsive protein kinase, is activated downstream of AMPK and that together, these kinases may regulate glucose uptake and subsequent myocardial glucose utilization (22,26,36,39). Despite this established role of AMPK/p38 MAPK in glucose uptake, it is not known whether AMPK and p38 MAPK form a functional signaling cascade in the regulation of glycogen metabolism and glycolysis.…”

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confidence: 99%

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p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5′-AMP-activated protein kinase

Jaswal¹,

Gandhi²,

Finegan³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Clanachan AS. p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5Ј-AMP-activated protein kinase. Am J Physiol Heart Circ Physiol 292: H1978 -H1985, 2007. First published December 15, 2006; doi:10.1152/ajpheart.01121.2006.-Adenosineinduced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis and by increases in activity of adenosine 5Ј-monophosphate-activated protein kinase (AMPK). Because p38 mitogen-activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors SB202190 and SB203580 on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2 ϫ 10-min ischemia followed by 5-min reperfusion). Phosphorylation of AMPK and p38 MAPK each were increased fourfold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580 occurred independently of any change in tissue ATP-to-AMP ratio and did not alter glucose uptake, but it was accompanied by an increase in glycogen synthesis and glycogen content and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine-induced cardioprotection in stressed hearts.adenosine; adenosine 5Ј-monophosphate-activated protein kinase; glycogen metabolism CARDIOPROTECTION INDUCED BY adenosine and the adenosine A 1 receptor agonist N 6 -cyclohexyladenosine may be related to their ability to stimulate glycogen synthesis and inhibit glycolysis and proton production during reperfusion following ischemia (7, 9). However, our laboratory has shown that in hearts stressed by transient ischemia, there is a loss of adenosineinduced cardioprotection (8), an effect consistent with the lower cardioprotective effectiveness of adenosine and adenosine mimetic agents in studies involving patients with coronary artery disease (24). Because this model of transient ischemia differs from ischemic preconditioning, in that the transient ischemia does not enhance the recovery of left ventricular (LV) function following severe ischemia (8), stressing by transient ischemia may provide a unique system in which to study the mechanisms underlying the loss of adenosine-induced cardioprotection observe...

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Preconditioning Enhanced Glucose Uptake Is Mediated by p38 MAP Kinase Not by Phosphatidylinositol 3-Kinase

Cited by 80 publications

References 50 publications

Role of AMP-activated protein kinase in healthy and diseased hearts

Role of AMP-activated protein kinase in healthy and diseased hearts

Thiazolidinedione Treatment Normalizes Insulin Resistance and Ischemic Injury in the Zucker Fatty Rat Heart

p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5′-AMP-activated protein kinase

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