Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.31 (AMP-activated protein kinase)
13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Though known as a sensor of energy balance, AMP-activated protein kinase (AMPK) was recently shown to limit damage and apoptotic activity and contribute to the late preconditioning in heart. Interleukin-6 was also reported to involve in anti-apoptosis and cardio-protection in myocardium. Interestingly, both AMPK activity and IL-6 level were increased in response to ischemia, hypertrophy and oxidative stress. To determine whether AMPK activation will promote IL-6 production, cardiac fibroblasts (CFs) from mice were incubated with AMPK activator, 5-aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR). The results demonstrated that AICAR time and dose-dependently stimulated IL-6 production by ELISA and immunofluorescence. Pretreatment with p38 mitogen-activated protein kinase (MAPK) inhibitor blocked AICAR-induced IL-6 production; furthermore, AICAR-activated p38 MAPK phosphorylation by Western blot. To confirm that the increase in IL-6 production is ascribed to AMPK activation, we used another known AMPK activator, metformin. It also dose-dependently potentiated IL-6 production in CFs, and this potentiation could be reversed by p38 MAPK inhibitor. In conclusion, AMPK activation promoted IL-6 production in CFs via p38 MAPK-dependent pathway.
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PMID:AICAR stimulates IL-6 production via p38 MAPK in cardiac fibroblasts in adult mice: a possible role for AMPK. 1622 18

Recent studies indicate that the LKB1 is a key regulator of the AMP-activated protein kinase (AMPK), which plays a crucial role in protecting cardiac muscle from damage during ischemia. We have employed mice that lack LKB1 in cardiac and skeletal muscle and studied how this affected the activity of cardiac AMPKalpha1/alpha2 under normoxic, ischemic, and anoxic conditions. In the heart lacking cardiac muscle LKB1, the basal activity of AMPKalpha2 was vastly reduced and not increased by ischemia or anoxia. Phosphorylation of AMPKalpha2 at the site of LKB1 phosphorylation (Thr172) or phosphorylation of acetyl-CoA carboxylase-2, a downstream substrate of AMPK, was ablated in ischemic heart lacking cardiac LKB1. Ischemia was found to increase the ADP-to-ATP (ADP/ATP) and AMP-to-ATP ratios (AMP/ATP) to a greater extent in LKB1-deficient cardiac muscle than in LKB1-expressing muscle. In contrast to AMPKalpha2, significant basal activity of AMPKalpha1 was observed in the lysates from the hearts lacking cardiac muscle LKB1, as well as in cardiomyocytes that had been isolated from these hearts. In the heart lacking cardiac LKB1, ischemia or anoxia induced a marked activation and phosphorylation of AMPKalpha1, to a level that was only moderately lower than observed in LKB1-expressing heart. Echocardiographic and morphological analysis of the cardiac LKB1-deficient hearts indicated that these hearts were not overtly dysfunctional, despite possessing a reduced weight and enlarged atria. These findings indicate that LKB1 plays a crucial role in regulating AMPKalpha2 activation and acetyl-CoA carboxylase-2 phosphorylation and also regulating cellular energy levels in response to ischemia. They also provide genetic evidence that an alternative upstream kinase can activate AMPKalpha1 in cardiac muscle.
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PMID:Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKalpha2 but not AMPKalpha1. 1633 22

Previous studies showed that insulin antagonizes AMP-activated protein kinase activation by ischemia and that protein kinase B might be implicated. Here we investigated whether the direct phosphorylation of AMP-activated protein kinase by protein kinase B might participate in this effect. Protein kinase B phosphorylated recombinant bacterially expressed AMP-activated protein kinase heterotrimers at Ser(485) of the alpha1-subunits. In perfused rat hearts, phosphorylation of the alpha1/alpha2 AMP-activated protein kinase subunits on Ser(485)/Ser(491) was increased by insulin and insulin pretreatment decreased the phosphorylation of the alpha-subunits at Thr(172) in a subsequent ischemic episode. It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser(485)/Ser(491) phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr(172) by LKB1 and the resulting activation of AMP-activated protein kinase.
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PMID:Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491. 1634 11

Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia. This increased expression was quantitatively reproduced in cardiac myocytes using a transgenic (TG) mouse model. After 45 minutes of coronary artery occlusion and reperfusion, hearts from TG mice showed an 82+/-5% reduction in infarct size compared with wild-type (WT), which was similar to the 84+/-4% reduction of infarct size observed in WT after a protocol of ischemic preconditioning. Hearts from TG mice showed significant activation of survival kinases participating in preconditioning, including Akt and the 5'AMP-activated protein kinase (AMPK). H11K directly binds to both Akt and AMPK and promotes their nuclear translocation and their association in a multiprotein complex, which results in a stimulation of survival mechanisms in cytosol and nucleus, including inhibition of proapoptotic effectors (glycogen synthase kinase-3beta, Bad, and Foxo), activation of antiapoptotic effectors (protein kinase Cepsilon, endothelial and inducible NO synthase isoforms, and heat shock protein 70), increased expression of the hypoxia-inducible factor-1alpha, and genomic switch to glucose utilization. Therefore, activation of survival pathways by H11K preemptively triggers the antiapoptotic and metabolic response to ischemia and is sufficient to confer cardioprotection in vivo equally potent to preconditioning.
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PMID:H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart. 1637 98

AMP-activated protein kinase (AMPK) plays a key role in the regulation of energy homeostasis and is activated in response to cellular stress, including hypoxia/ischemia and hyperglycemia. The stress events are accompanied by rapid release of extracellular nucleotides from damaged tissues or activated endothelial cells (EC) and platelets. We demonstrate that extracellular nucleotides (ATP, ADP, and UTP, but not UDP) and adenosine independently induce phosphorylation and activation of AMPK in human umbilical vein EC (HUVEC) by the mechanism that is not linked to changes in AMP:ATP ratio. HUVEC express NTPDases, as well as 5'-nucleotidase; hence, nucleotides can be metabolized to adenosine. However, inhibition of 5'-nucleotidase had no effect on ATP/ADP/UTP-induced phospho- rylation of AMPK, indicating that AMPK activation occurred as a direct response to nucleotides. Nucleotide-evoked phosphorylation of AMPK in HUVEC was mediated by P2Y1, P2Y2, and/or P2Y4 receptors, whereas P2Y6, P2Y11, and P2X receptors were not involved. The nucleotide-induced phosphorylation of AMPK was affected by changes in the concentration of intracellular Ca2+ and by Ca2+/calmodulin-dependent kinase kinase (CaMKK), although most likely it was not dependent on LKB1 kinase. Adenosine-induced phosphorylation of AMPK was not mediated by P1 receptors but required adenosine uptake by equilibrative nucleoside transporters followed by its (intracellular) metabolism to AMP. Moreover, adenosine effect was Ca2+ and CaMKK independent, although probably associated with upstream LKB1. We hypothesize that P2 receptors and adenosine transporters could be novel targets for the pharmacological regulation of AMPK activity and its downstream effects on EC function.
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PMID:Extracellular nucleotides and adenosine independently activate AMP-activated protein kinase in endothelial cells: involvement of P2 receptors and adenosine transporters. 1649 86

AMP-activated protein kinase (AMPK) plays a key role in modulating cellular metabolic processes. AMPK, a serine-threonine kinase, is a heterotrimeric complex of catalytic alpha-subunits and regulatory beta- and gamma-subunits with multiple isoforms. Mutations in the cardiac gamma(2)-isoform have been associated with hypertrophic cardiomyopathy and pre-excitation syndromes. However, physiological regulation of AMPK complexes containing different subunit isoforms is not well defined and is important for an understanding of the function of this signaling pathway in the intact heart. We evaluated the kinase activity associated with heart AMPK complexes containing specific alpha- and gamma-subunit isoforms of AMPK in an in vivo rat model of regional ischemia. Left coronary artery occlusion activated the immunoprecipitated alpha(1)-isoform (6-fold, P < 0.01) and alpha(2)-isoform (9-fold, P < 0.01) in the ischemic left ventricle compared with sham controls. The degree of alpha-subunit activation depended on the extent of ischemia and paralleled echocardiographic contractile dysfunction. The regulatory gamma(1)- and gamma(2)-isoforms were expressed in the heart. The gamma(1)- and gamma(2)-isoforms coimmunoprecipitated with alpha(1)- and alpha(2)-isoforms in proportion to alpha-subunit content. gamma(1)-Isoform immunocomplexes accounted for 70% of AMPK activity and AMPK phosphorylation (Thr(172)) in hearts. Ischemia similarly increased AMPK activity associated with the gamma(1)- and gamma(2)-isoform complexes threefold (P < 0.01 for each). Thus AMPK catalytic alpha(1)- and alpha(2)-isoforms are activated by regional ischemia in vivo in the heart, irrespective of the regulatory gamma(1)- or gamma(2)-isoforms to which they are complexed. Despite the pathophysiological importance of gamma(2)-isoform mutations, gamma(1)-isoform complexes account for most of the AMPK activity in the ischemic heart.
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PMID:Activation of AMPK alpha- and gamma-isoform complexes in the intact ischemic rat heart. 1664 75

Loss of cardioprotection by adenosine in hearts stressed by transient ischemia may be due to its effects on glucose metabolism. In the absence of transient ischemia, adenosine inhibits glycolysis, whereas it accelerates glycolysis after transient ischemia. Inasmuch as 5'-AMP-activated protein kinase (AMPK) is implicated as a regulator of glucose and fatty acid utilization, this study determined whether a differential alteration of AMPK activity contributes to acceleration of glycolysis by adenosine in hearts stressed by transient ischemia. Studies were performed in working rat hearts perfused aerobically under normal conditions or after transient ischemia (two 10-min periods of ischemia followed by 5 min of reperfusion). LV work was not affected by adenosine. AMPK phosphorylation was not affected by transient ischemia; however, phosphorylation and activity were increased nine- and threefold, respectively, by adenosine in stressed hearts. Phosphorylation of acetyl-CoA carboxylase and rates of palmitate oxidation were unaltered. Glycolysis and calculated proton production were increased 1.8- and 1.7-fold, respectively, in hearts with elevated AMPK activity. Elevated AMPK activity was associated with inhibition of glycogen synthesis and unchanged rates of glucose uptake and glycogenolysis. Phentolamine, an alpha-adrenoceptor antagonist, which prevents adenosine-induced activation of glycolysis in stressed hearts, prevented AMPK phosphorylation. These data demonstrate that adenosine-induced activation of AMPK after transient ischemia is not sufficient to alter palmitate oxidation or glucose uptake. Rather, activation of AMPK alters partitioning of glucose away from glycogen synthesis; the increase in glycolysis may in part contribute to loss of adenosine-induced cardioprotection in hearts subjected to transient ischemia.
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PMID:Effects of adenosine on myocardial glucose and palmitate metabolism after transient ischemia: role of 5'-AMP-activated protein kinase. 1664 81

The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is activated by acute increases in the cellular [AMP]/[ATP] ratio. In skeletal and/or cardiac muscle, AMPK activity is increased by stimuli such as exercise, hypoxia, ischemia, and osmotic stress. There are many lines of evidence that increasing AMPK activity in skeletal muscle results in increased rates of glucose transport. Although similar to the effects of insulin to increase glucose transport in muscle, it is clear that the underlying mechanisms for AMPK-mediated glucose transport involve proximal signals that are distinct from that of insulin. Here, we discuss the evidence for AMPK regulation of glucose transport in skeletal and cardiac muscle and describe research investigating putative signaling mechanisms mediating this effect. We also discuss evidence that AMPK may play a role in enhancing muscle and whole body insulin sensitivity for glucose transport under conditions such as exercise, as well as the use of the AMPK activator AICAR to reverse insulin-resistant conditions. The identification of AMPK as a novel glucose transport mediator in skeletal muscle is providing important insights for the treatment and prevention of type 2 diabetes.
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PMID:AMP-activated protein kinase and the regulation of glucose transport. 1682 58

A novel niacin-bound, chromium-based energy formula (EF; InterHealth Nutraceuticals, Benicia, CA) has been developed in conjunction with D-ribose, caffeine, ashwagandha extract (containing 5% withanolides), and selected amino acids. We have assessed the efficacy of oral administration of EF (40 mg x kg body wt(-1) x day(-1)) in male and female rats over a period of 90 consecutive days on the cardiovascular and pathophysiological functions in an isolated rat heart model. After 30, 60, and 90 days of treatment with EF, the hearts of male and female rats were subjected to 30 min of global ischemia followed by 2 h of reperfusion and were measured for myocardial ATP, creatine phosphate (CP), phosphorylated AMP kinase (p-AMPK), and heat shock proteins. Myocardial ATP and CP levels were increased in both male and female rats after EF treatment compared with the controls. Western blot analyses were performed to quantify the expression of stress-related proteins such as heat shock proteins (HSP-70, -32, and -25) and are found to be increased in both male and female rats after EF treatment. The p-AMPK level, which is a sensor for the energy state in various cell types, was also found to be increased after treatment with EF in both male and female rats. Aortic flow, maximum first derivative of developed pressure, left ventricular developed pressure, and infarct size were observed after ischemia-reperfusion and found to be significantly improved in EF-treated rats compared with control animals. Thus EF demonstrated long-term safety as well as exhibiting significant cardioprotective ability during ischemia and reperfusion injury by increased energy production, improved cardiac function, and reduced infarct size.
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PMID:Niacin-bound chromium enhances myocardial protection from ischemia-reperfusion injury. 1684 Jul 37

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.
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PMID:Role of AMP-activated protein kinase in healthy and diseased hearts. 1684 22


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