Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia is a critical event for higher organisms, and cells and tissues react by increasing the oxygen supply by vasodilatation, angiogenesis, and erythropoiesis and maintaining cellular energy by increasing glycolysis and inhibiting anabolic pathways. Stimulation of glycolysis has been regarded as the main response that increases energy production during hypoxia; however, there is an obvious conflict during ischemia, because both the oxygen and glucose supply are insufficient. In this study, we found that exposure of HepG2 cells and normal fibroblasts to hypoxia induces cellular tolerance to glucose starvation. The tolerance induced by hypoxia is dependent on several amino acids, indicating a switch from glucose to amino acids as the energy source. When antisense RNA expression vector for 5'-AMP-activated protein kinase or protein kinase B/Akt was transfected into HepG2 cells, the induction of tolerance to glucose was greatly inhibited, indicating that the tolerance was dependent on 5'-AMP-activated protein kinase and protein kinase B/Akt. Similar tolerance was induced by nitric oxide exposure. The tolerance induced was observed in various cells and may represent a previously unknown physiological response related to hypoxia-preconditioning and tumor progression:austerity.
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PMID:Hypoxia and nitric oxide treatment confer tolerance to glucose starvation in a 5'-AMP-activated protein kinase-dependent manner. 1209 79

The stimulation of heart glycolysis by insulin and ischemia involves the recruitment of the glucose transporter GLUT4 to the plasma membrane and the activation of 6-phosphofructo-2-kinase (PFK-2), which in turn increases the concentration of fructose 2,6-bisphosphate, a well-known stimulator of glycolysis. This review focuses on the mechanisms responsible for PFK-2 activation by insulin and ischemia in heart. Heart PFK-2 is phosphorylated by various protein kinases, including protein kinase B (PKB), thought to mediate most, if not all, short-term effects of insulin, and the AMP-activated protein kinase (AMPK), known to be activated under anaerobic conditions. We found that PKB is not required for PFK-2 activation by insulin and we partially purified an insulin-sensitive PFK-2 kinase, that differs from PKB and from other insulin-stimulated protein kinases. We also demonstrated that AMPK mediates PFK-2 activation by ischemia. Finally, our study of the interaction between the signaling pathways of insulin and ischemia revealed opposite effects on signaling. Intracellular acidosis induced by ischemia inhibited insulin signaling, whereas insulin pretreatment antagonized AMPK activation by ischemia.
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PMID:Insulin and ischemia stimulate glycolysis by acting on the same targets through different and opposing signaling pathways. 1239 81

Abnormally high rates of fatty acid metabolism is an important contributor to the severity of ischemic heart disease. During and following myocardial ischemia a number of alterations in fatty acid oxidation occur that result in an excessive amount of fatty acids being used as a fuel source by the heart. This contributes to a decrease in cardiac efficiency both during and following the ischemic episode. Central to the regulation of fatty acid oxidation in the heart is malonyl CoA, which is a potent endogenous inhibitor of mitochondrial fatty acid uptake. The levels of malonyl CoA are regulated both by its synthesis by acetyl CoA carboxylase (ACC) and its degradation by malonyl CoA decarboxylase (MCD). ACC is in turn controlled by AMP-activated protein kinase (AMPK), which acts as a fuel gauge in the heart. The control of these enzymes are altered during ischemia, such that malonyl CoA levels in the heart decrease, resulting in an increased relative contribution of fatty acids to oxidative metabolism. Activation of AMPK during and following ischemia appears to be centrally involved in this decrease in malonyl CoA. Clinical evidence is now accumulating that show that inhibition of fatty acid oxidation is an effective approach to treating ischemic heart disease. As a result, modulation of fatty acid oxidation by targeting the enzymes controlling malonyl CoA may be a novel approach to treating angina pectoris and acute myocardial infarction. This paper will discuss some of the molecular changes that occur in fatty acid oxidation in the ischemic heart and will include a discussion of the important role of malonyl CoA in this process.
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PMID:Malonyl CoA control of fatty acid oxidation in the ischemic heart. 1239 82

By phosphorylating target proteins, AMP-activated protein kinase (AMPK) inhibits ATP-utilizing proteins and activates ATP-synthesizing proteins, thereby increasing ATP synthesis under conditions such as hypoxia and ischemia. It has been proposed that AMPK also phosphorylates and inhibits creatine kinase (CK), the enzyme which catalyzes the reversible transfer of a phosphoryl group between creatine and ADP. Here, we examine the hypothesis that AMPK inactivates CK activity under three conditions where [AMP] and AMP-dependent AMPK velocity increase: increased workload both in the isolated rat heart and in the living rat, hypoxia in the living rat heart and low-flow ischemia in the isolated red blood cell perfused rat heart. For the experiments varying workload in the isolated rat heart (both ejecting and isovolumic models), we also changed oxidizable substrate available to the isolated heart in order to vary the [AMP]/[ATP]. CK reaction velocity in the intact rat heart was directly measured using (31)P magnetization transfer. The metabolically active AMP and ATP pools were determined from (31)P NMR measurements and we calculate AMP-dependent AMPK velocity from the Michaelis-Menten relationship. We found that under normoxic conditions where [AMP] and AMPK velocity increase, the linear relationship between CK and AMPK velocities is positive, not inverse. Under conditions of low pO(2) (hypoxia and low-flow ischemia), CK velocity fell 2-4-fold while the increase in AMP-activated AMPK activity was modest. This analysis illustrates the complex nature of AMPK regulation in the heart.
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PMID:Is creatine kinase a target for AMP-activated protein kinase in the heart? 1239 83

Myocardial ischemia is the leading cause of all cardiovascular deaths in North America. Myocardial ischemia is accompanied by profound changes in metabolism including alterations in glucose and fatty acid metabolism, increased uncoupling of glucose oxidation from glycolysis and accumulation of protons within the myocardium. These changes can contribute to a poor functional recovery of the heart. One key player in the ischemia-induced alteration in fatty acid and glucose metabolism is 5'AMP-activated protein kinase (AMPK). Accumulating evidence suggest that activation of AMPK during myocardial ischemia both increases glucose uptake and glycolysis while also increasing fatty acid oxidation during reperfusion. Gain-of-function mutations of AMPK in cardiac muscle may also be causally related to the development of hypertrophic cardiomyopathies. Therefore, a better understanding of role of AMPK in cardiac metabolism is necessary to appropriately modulate its activity as a potential therapeutic target in treating ischemia reperfusion injuries. This review attempts to update some of the recent findings that delineate various pathways through which AMPK regulates glucose and fatty acid metabolism in the ischemic myocardium.
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PMID:AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart. 1268 19

AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that plays a pivotal role in regulating cellular metabolism for sustaining energy homeostasis under stress conditions. Activation of AMPK has been observed in the heart during acute and chronic stresses, but its functional role has not been completely understood because of the lack of effective activators and inhibitors of this kinase in the heart. We generated transgenic mice (TG) with cardiac-specific overexpression of a dominant negative mutant of the AMPK alpha2 catalytic subunit to clarify the functional role of this kinase in myocardial ischemia. In isolated perfused hearts subjected to a 10-min ischemia, AMPK alpha2 activity in wild type (WT) increased substantially (by 4.5-fold), whereas AMPK alpha2 activity in TG was similar to the level of WT at base line. Basal AMPK alpha1 activity was unchanged in TG and increased normally during ischemia. Ischemia stimulated a 2.5-fold increase in 2-deoxyglucose uptake over base line in WT, whereas the inactivation of AMPK alpha2 in TG significantly blunted this response. Using 31P NMR spectroscopy, we found that ATP depletion was accelerated in TG hearts during no-flow ischemia, and these hearts developed left ventricular dysfunction manifested by an early and more rapid increase in left ventricular end-diastolic pressure. The exacerbated ATP depletion could not be attributed to impaired glycolytic ATP synthesis because TG hearts consumed slightly more glycogen during this period of no-flow ischemia. Thus, AMPK alpha2 is necessary for maintaining myocardial energy homeostasis during ischemia. It is likely that the functional role of AMPK in myocardial energy metabolism resides both in energy supply and utilization.
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PMID:Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase. 1276 62

All cells must maintain a high ratio of cellular ATP:ADP to survive. Because of the adenylate kinase reaction (2ADP <--> ATP + AMP), AMP rises whenever the ATP:ADP ratio falls, and a high cellular ratio of AMP:ATP is a signal that the energy status of the cell is compromised. The AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that is switched on by a rise in the AMP:ATP ratio, via a complex mechanism that results in an exquisitely sensitive system. AMPK is switched on by cellular stresses that either interfere with ATP production (e.g. hypoxia, glucose deprivation, or ischemia) or by stresses that increase ATP consumption (e.g. muscle contraction). It is also activated by hormones that act via Gq-coupled receptors, and by leptin and adiponectin, via mechanisms that remain unclear. Once activated, the system switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes that are not essential for short-term cell survival, such as the synthesis of lipids, carbohydrates, and proteins. The AMPK cascade is the probable target for the antidiabetic drug metformin, and current indications are that it is responsible for many of the beneficial effects of exercise in the treatment and prevention of type 2 diabetes and the metabolic syndrome.
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PMID:Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. 1296 15

The heart responds to energetic stress with both acute and chronic changes in substrate metabolism. Recent work has demonstrated that the metabolic stress kinase AMP-activated protein kinase (AMPK) plays an important role in the acute regulation of carbohydrate and fatty acid metabolism in the setting of acute energetic stressors, such as ischemia/reperfusion, or increased workload, through covalent and noncovalent regulation of enzymes involved in intermediary metabolism. In addition, chronic activation of AMPK has been shown to affect the expression of key proteins regulating carbohydrate and fatty acid metabolism. Characterizing the effects of AMPK will provide important insights into its function in the normal heart and might provide new metabolic therapies for ischemic heart disease and heart failure.
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PMID:The Role of AMP-activated protein kinase in fuel selection by the stressed heart. 1459 64

The AMP-activated protein kinase (AMPK) exists as a heterotrimetric complex comprising a catalytic alpha subunit and non-catalytic beta and gamma subunits. Under conditions of hypoxia, exercise, ischemia, heat shock, and low glucose, AMPK is activated allosterically by rising cellular AMP and by phosphorylation of the catalytic alpha subunit. The mammalian target of rapamycin (mTOR) controls cellular functions in response to amino acids and growth factors. Recent reports including our study have demonstrated the possible interplay between mTOR and AMPK signaling pathways, supporting a model in which mitochondrial dysfunction caused by the mitochondrial inhibitors or ATP depletion inhibits activation of p70 S6 kinase alpha (p70alpha), a downstream effector of mTOR, by activating AMPK. Leucine may stimulate p70alpha phosphorylation via mTOR pathway, in part, by serving both as a mitochondrial fuel through oxidative carboxylation and an allosteric activation of glutamate dehydrogenase. This hypothesis may support an idea in which leucine modulates mTOR function, in part by regulating mitochondrial function and AMPK. Further understanding of the role of mTOR in coordinating amino acid- and energy-sensing pathways would provide new insights into relationship between nutrients and cellular functions.
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PMID:mTOR integrates amino acid- and energy-sensing pathways. 1468 82

AMP-activated protein kinase (AMPK) is a serine-threonine kinase that regulates cellular metabolism and has an essential role in activating glucose transport during hypoxia and ischemia. The mechanisms responsible for AMPK stimulation of glucose transport are uncertain, but may involve interaction with other signaling pathways or direct effects on GLUT vesicular trafficking. One potential downstream mediator of AMPK signaling is the nitric oxide pathway. The aim of this study was to examine the extent to which AMPK mediates glucose transport through activation of the nitric oxide (NO)-signaling pathway in isolated heart muscles. Incubation with 1 mM 5-amino-4-imidazole-1-beta-carboxamide ribofuranoside (AICAR) activated AMPK (P < 0.01) and stimulated glucose uptake (P < 0.05) and translocation of the cardiomyocyte glucose transporter GLUT4 to the cell surface (P < 0.05). AICAR treatment increased phosphorylation of endothelial NO synthase (eNOS) approximately 1.8-fold (P < 0.05). eNOS, but not neuronal NOS, coimmunoprecipitated with both the alpha(2) and alpha(1) AMPK catalytic subunits in heart muscle. NO donors also increased glucose uptake and GLUT4 translocation (P < 0.05). Inhibition of NOS with N(omega)-nitro-l-arginine and N(omega)-methyl-l-arginine reduced AICAR-stimulated glucose uptake by 21 +/- 3% (P < 0.05) and 25 +/- 4% (P < 0.05), respectively. Inhibition of guanylate cyclase with ODQ and LY-83583 reduced AICAR-stimulated glucose uptake by 31 +/- 4% (P < 0.05) and 22 +/- 3% (P < 0.05), respectively, as well as GLUT4 translocation to the cell surface (P < 0.05). Taken together, these results indicate that activation of the NO-guanylate cyclase pathway contributes to, but is not the sole mediator of, AMPK stimulation of glucose uptake and GLUT4 translocation in heart muscle.
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PMID:Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. 1526 62


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