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: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence suggests that glucagon-like peptide-1 (GLP-1) enhances recovery of left ventricular (LV) function after transient coronary artery occlusion. However, it is uncertain whether GLP-1 has direct effects on normal or ischemic myocardium and whether the mechanism involves increased myocardial glucose uptake. LV function and myocardial glucose uptake and lactate production were measured under basal conditions and after 30 min of low-flow ischemia and 30 min of reperfusion in the presence and absence of GLP-1-(7-36) amide. The response was compared with standard buffer alone or buffer containing insulin (100 microU/ml). GLP-1 decreased the left ventricular developed pressure (baseline: 100 +/- 2 mm Hg; GLP-1: 75 +/- 3 mm Hg, p < 0.05) and LV dP/dt (baseline: 4876 +/- 65 mm Hg/s; GLP-1: 4353 +/- 76 mm Hg/s, p < 0.05) in normal hearts. GLP-1 increased myocardial glucose uptake (baseline: 33 +/- 3 micromol/min/g; GLP-1: 81 +/- 7 micromol/min/g, p < 0.05) by increasing nitric oxide production and glucose transporter (GLUT)-1 translocation. GLP-1 enhanced recovery after 30 min of low-flow ischemia with significant improvements in LV end-diastolic pressure (control: 13 +/- 4 mm Hg; GLP-1: 3 +/- 2 mm Hg, p < 0.05) and LV developed pressure (control: 66 +/- 6 mm Hg; GLP-1: 98 +/- 5 mm Hg, p < 0.05). GLP-1 increased LV function, myocardial glucose uptake, and GLUT-1 and GLUT-4 translocation during reperfusion to an extent similar to that with insulin. GLP-1 has direct effects on the normal heart, reducing contractility, but increasing myocardial glucose uptake through a non-Akt-1-dependent mechanism, distinct from the actions of insulin. However, GLP-1 increased myocardial glucose uptake and enhanced recovery of cardiac function after low-flow ischemia in a fashion similar to that of insulin.
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PMID:Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. 1648 28

Brain astrocytes provide structural and metabolic support to surrounding cells during ischemia. Glucose and oxygen are critical to brain function, and glucose uptake and metabolism by astrocytes are essential to their metabolic coupling to neurons. To examine astrocyte metabolic response to hypoxia, cell survival and metabolic parameters were assessed in rat primary cortical astrocytes cultured for 3 weeks in either normoxia or in either 1 day or 3 weeks sustained hypoxia (5% O2). Although cell survival and proliferation were not affected by the mildly hypoxic environment, substantial differences in glucose consumption and lactate release after either acute or prolonged hypoxia suggest that astrocyte metabolism may contribute to their adaptation. Hypoxia over a period of 1 day increased glucose uptake, lactate release, and glucose transporter 1 (GLUT1) and monocarboxylate transporter 1 (MCT1) expression, whereas hypoxia over a period of 3 weeks resulted in a decrease of all parameters. Furthermore, increased glucose uptake at 1 day of hypoxia was not inhibited by cytochalasin B suggesting the involvement of additional glucose transporters. We uncovered hypoxia-regulated expression of sodium-dependent glucose transporters (SGLT1) in astrocytes indicating a novel adaptive strategy involving both SGLT1 and GLUT1 to regulate glucose intake in response to hypoxia. Overall, these findings suggest that although increased metabolic response is required for the onset of astrocyte adaptation to hypoxia, prolonged hypoxia requires a shift to an energy conservation mode. These findings may contribute to the understanding of the relative tolerance of astrocytes to hypoxia compared with neurons and provide novel therapeutic strategies aimed at maintaining brain function in cerebral pathologies involving hypoxia.
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PMID:Differential metabolic adaptation to acute and long-term hypoxia in rat primary cortical astrocytes. 1657 48

The mechanisms underlying functional recovery after stroke are poorly understood. Brain-adaptive responses to the hypoxic stress elicited by ischemia could contribute to these mechanisms. Indeed, hypoxia-inducible factor-1 (HIF-1), one of the main transcriptional factors regulated by oxygen level, increases the expression of several beneficial genes such as erythropoietin, glucose transporter-1 and vascular endothelial growth factor. In order to strengthen the expression of these hypoxia-inducible factors, we administered deferoxamine, an iron chelator known to stabilize HIF-1alpha protein expression, and examined its effects on the functional deficits induced by ischemia. Anesthetized Sprague-Dawley rats were subjected to 60 min of intraluminal occlusion of the middle cerebral artery. Chronic deferoxamine treatment (300 mg/kg, s.c.), or its vehicle, started 24 h after ischemia and was continued bi-weekly until the animals were killed. Sensorimotor deficits were periodically assessed over 2 months, and at this end point, the lesion volume was determined by histology. Treatment with deferoxamine significantly decreased the size of brain damage (-28%) after ischemia and improved behavioral recovery. Indeed, neurological score and sensorimotor performances in the adhesive removal test recovered earlier in the deferoxamine-treated animals. Moreover, the long-lasting skilled forepaw reaching deficits were attenuated by deferoxamine. Although an antioxidant effect of deferoxamine cannot be excluded, the hypothesis that its beneficial effects could be mediated by an increase in HIF-1 target genes merits further investigations. Our data suggest that delayed administration of deferoxamine could represent an interesting therapeutical approach to treat focal cerebral ischemia.
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PMID:Delayed administration of deferoxamine reduces brain damage and promotes functional recovery after transient focal cerebral ischemia in the rat. 1662 32

Recently, mounting evidence has emerged to suggest that hyperbaric oxygenation (HBOT)-induced neuroprotection after experimental global ischemia and subarachnoid hemorrhage entails a decrease in the expression of hypoxia-inducible factor-1alpha (HIF-1alpha). Therefore, the purpose of this study was to test the hypothesis that oxygen-induced neuroprotection after neonatal hypoxia-ischemia involves alterations in the expression of HIF-1alpha. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 h of hypoxia (8% O(2) at 37 degrees C). Pups were then treated with HBOT (2.5 ATA) or normobaric oxygenation treatment (NBOT) for 2 h. The expression and phosphorylation status of HIF-1alpha was evaluated at intervals up to 24 h after the insult, as was the expression of glucose transporter (GLUT)-1, GLUT-3, lactate dehydrogenase (LDH), aldolase (Ald), and p53. The protein-protein interaction of HIF-1alpha and p53 was also examined. An elevated expression of HIF-1alpha, GLUT-1, GLUT-3, Ald, and LDH was observed after the insult. An increase in the dephosphorylated form of HIF-1alpha was followed by an increase in the association of HIF-1alpha with p53 and an increase in p53 levels. Both HBOT and NBOT reduced the elevated expression of HIF-1alpha and decreased its dephosphorylated form. Furthermore, both treatments promoted a transient increase in the expression of GLUT-1, GLUT-3, LDH, and Ald, while decreasing the HIF-1alpha-p53 interaction and decreasing the expression of p53. Therefore, the alteration of the HIF-1alpha phenotype by a single oxygen treatment may be one of the underlying mechanisms for the observed oxygen-induced neuroprotection seen when oxygen is administered after a neonatal hypoxic-ischemic insult.
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PMID:Oxygen treatment after experimental hypoxia-ischemia in neonatal rats alters the expression of HIF-1alpha and its downstream target genes. 1672 20

Severe sepsis is accompanied by acute renal failure (ARF) with renal tubular dysfunction and glucosuria. In this study, we aimed to determine the regulation of renal tubular glucose transporters during severe experimental inflammation. Male C57BL/6J mice were injected with LPS or proinflammatory cytokines, and renal perfusion, glomerular filtration rate (GFR), fractional glucose excretion, and expression of tubular glucose transporters were determined. We found a decreased plasma glucose concentration with impaired renal tissue perfusion and GFR and increased fractional glucose excretion associated with decreased expression of SGLT2, SGLT3, and GLUT2 after LPS injection. Similar alterations were observed after application of TNF-alpha, IL-1beta, IL-6, or IFN-gamma. To clarify the role of proinflammatory cytokines, we performed LPS injections in knockout mice with deficiencies for TNF-alpha, IL-1 receptor type 1, IFN-gamma, or IL-6 as well as LPS injections in glucocorticoid-treated wild-type mice. LPS-induced alterations of glucose transporters also were present in single-cytokine knockout mice. In contrast, glucocorticoid treatment clearly attenuated LPS-induced changes in renal glucose transporter expression and improved GFR and fractional glucose excretion. LPS-induced decrease of renal perfusion was not improved by glucocorticoids, indicating a minor role of ischemia in the development of septic renal dysfunction. Our results demonstrate modifications of tubular glucose transporters during severe inflammation that are probably mediated by proinflammatory cytokines and account for the development of ARF with increased fractional glucose excretion. In addition, our findings provide an explanation why single anti-cytokine strategies fail in the therapy of septic patients and contribute to an understanding of the beneficial effects of glucocorticoids on septic renal dysfunction.
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PMID:Regulation of renal glucose transporters during severe inflammation. 1703 38

Restoration of local blood supply in the post-ischemic brain plays a critical role in tissue repair and functional recovery. The present investigation explored beneficial effects of recombinant human erythropoietin (rhEPO) on vascular endothelial cell survival, angiogenesis, and restoration of local cerebral blood flow (LCBF) after permanent focal cerebral ischemia in adult mice. Saline or rhEPO (5,000 U/kg, intraperitoneal) was administered 30 mins before ischemia and once daily after ischemic stroke. Immunohistochemistry showed an enhancing effect of rhEPO on expression of EPO receptor (EPOR) of endothelial cells in the penumbra region 3 to 21 days after the ischemic insult. The treatment with rhEPO decreased ischemia-induced cell death and infarct volume 3 days after stroke. Specifically, rhEPO reduced the number of terminal deoxynucleotidyl transferase biotin-dUPT nick end labeling- and caspase-3-positive endothelial cells in the penumbra region. Colocalization of the vessel marker glucose transporter-1 (Glut-1) and cell proliferation marker 5-bromo-2'-deoxyuridine indicated enhanced angiogenic activity in rhEPO-treated mice 7 to 21 days after stroke. Western blot showed upregulation of the expression of angiogenic factors Tie-2, Angiopoietin-2, and vascular endothelial growth factor in rhEPO-treated animals. Local cerebral blood flow was measured by laser scanning imaging 3 to 21 days after stroke. At 14 days, LCBF in the penumbra was recovered to preischemia levels in rhEPO-treated mice but not in control mice. Our data suggest that rhEPO treatment upregulates the EPOR level in vascular endothelial cells, confers neurovascular protection, and enhances angiogenesis. We further show a promoting effect of rhEPO on LCBF recovery in the ischemic brain. These rhEPO-induced effects may contribute to therapeutic benefits in the treatment of ischemic stroke.
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PMID:Erythropoietin-induced neurovascular protection, angiogenesis, and cerebral blood flow restoration after focal ischemia in mice. 1707 15

Whereas glucose transporter 1 (GLUT-1) is thought to be responsible for basal glucose uptake in cardiac myocytes, little is known about its relative distribution between the different plasma membranes and cell types in the heart. GLUT-4 translocates to the myocyte surface to increase glucose uptake in response to a number of stimuli. The mechanisms underlying ischemia- and insulin-mediated GLUT-4 translocation are known to be different, raising the possibility that the intracellular destinations of GLUT-4 following these stimuli also differ. Using immunogold labeling, we describe the cellular localization of these two transporters and investigate whether insulin and ischemia induce differential translocation of GLUT-4 to different cardiac membranes. Immunogold labeling of GLUT-1 and GLUT-4 was performed on left ventricular sections from isolated hearts following 30 min of either insulin, ischemia, or control perfusion. In control tissue, GLUT-1 was predominantly (76%) localized in the capillary endothelial cells, with only 24% of total cardiac GLUT-1 present in myocytes. GLUT-4 was found predominantly in myocytes, distributed between sarcolemmal and T tubule membranes (1.84 +/- 0.49 and 1.54 +/- 0.33 golds/microm, respectively) and intracellular vesicles (127 +/- 18 golds/microm(2)). Insulin increased T tubule membrane GLUT-4 content (2.8 +/- 0.4 golds/microm, P < 0.05) but had less effect on sarcolemmal GLUT-4 (1.72 +/- 0.53 golds/microm). Ischemia induced greater GLUT-4 translocation to both membrane types (4.25 +/- 0.84 and 4.01 +/- 0.27 golds/microm, respectively P < 0.05). The localization of GLUT-1 suggests a significant role in transporting glucose across the capillary wall before myocyte uptake via GLUT-1 and GLUT-4. We demonstrate independent spatial translocation of GLUT-4 under insulin or ischemic stimulation and propose independent roles for T-tubular and sarcolemmal GLUT-4.
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PMID:Immunogold labeling study of the distribution of GLUT-1 and GLUT-4 in cardiac tissue following stimulation by insulin or ischemia. 1718 52

Glucose uptake in the heart is mediated by specific glucose transporters (GLUTs) present on cardiomyocyte cell surface membranes. Metabolic stress and insulin both increase glucose transport by stimulating the translocation of glucose transporters from intracellular storage vesicles to the cell surface. Isolated perfused transgenic mouse hearts are commonly used to investigate the molecular regulation of heart metabolism; however, current methods to quantify cell surface glucose transporter content in intact mouse hearts are limited. Therefore, we developed a novel technique to directly assess the cell surface content of the cardiomyocyte glucose transporter GLUT4 in perfused mouse hearts, using a cell surface impermeant biotinylated bis-glucose photolabeling reagent (bio-LC-ATB-BGPA). Bio-LC-ATB-BGPA was infused through the aorta and cross-linked to cell surface GLUTs. Bio-LC-ATB-BGPA-labeled GLUT4 was recovered from cardiac membranes by streptavidin isolation and quantified by immunoblotting. Bio-LC-ATB-BGPA-labeling of GLUT4 was saturable and competitively inhibited by d-glucose. Stimulation of glucose uptake by insulin in the perfused heart was associated with parallel increases in bio-LC-ATB-BGPA-labeling of cell surface GLUT4. Bio-LC-ATB-BGPA also labeled cell surface GLUT1 in the perfused heart. Thus, photolabeling provides a novel approach to assess cell surface glucose transporter content in the isolated perfused mouse heart and may prove useful to investigate the mechanisms through which insulin, ischemia, and other stimuli regulate glucose metabolism in the heart and other perfused organs.
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PMID:Infusion of a biotinylated bis-glucose photolabel: a new method to quantify cell surface GLUT4 in the intact mouse heart. 1734 50

Cerebral ischemia disrupts the neurovascular unit, involving death of neuronal, glial, and endothelial cells (ECs) in the core and penumbra regions. Whereas the neuroprotective effect of recombinant human erythropoietin (rhEPO) has been widely investigated, its effects on ECs remain elusive. We now report the effects of rhEPO treatment on EC death and neurovasculature repair following a focal ischemic stroke in postnatal day 7 neonatal rats. rhEPO (5000 U/kg i.p.) was administered 60 min after ischemia and for the next 3 days. Western blot analysis revealed increased expression of neurovascular remodeling proteins, including Tie-1, angiopoietin-2, and basic fibroblast growth factor in rhEPO-treated pups. rhEPO treatment significantly reduced EC death in the ischemic penumbra region 12 to 72 h after ischemia examined by immunostaining of terminal deoxynucleotidyl transferase dUTP nick-end labeling and EC marker glucose transporter-1 (GLUT-1). Treatment with rhEPO increased proliferation of ECs and neuronal cells, revealed by costaining of 5-bromo-2'-deoxyuridine with GLUT-1 or with the neuronal marker protein (NeuN) 7 to 21 days after stroke. Specifically, rhEPO increased number of NeuN-positive cells in close proximity to proliferating microvessels. These results suggest for the first time that, in addition to its protection on neural cells, EPO protects ECs and promotes the neurovascular unit repair, which may contribute to its therapeutic benefits after neonatal ischemic stroke.
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PMID:The effect of recombinant human erythropoietin on neurovasculature repair after focal ischemic stroke in neonatal rats. 1749 64

A number of epidemiological and animal studies have suggested a cardioprotective role for estrogen. This review will focus on the cardioprotective role of estrogen in ischemia-reperfusion injury. Estrogen binding to receptors can lead to altered gene expression and estrogen has been shown to induce expression of a number of genes that have been suggested to be important in cardioprotection. Estrogen is reported to increase expression of the plasma membrane glucose transporter GLUT4 and to increase carbohydrate metabolism. Estrogen has also been reported to increase mitochondrial biogenesis and to alter mitochondrial generation of reactive oxygen species. Estrogen results in upregulation of cardiac eNOS and nNOS, which have been shown previously to be important mediators of cardioprotection. Nitric oxide has been shown to result in S-nitrosylation and inhibition of the L-type calcium channel, thereby reducing calcium loading during ischemia. Nitric oxide has also been reported to inhibit complex I and inhibition of complex I has been reported to reduce activation of the mitochondrial permeability transition pore. Nitric oxide has been shown to result in activation of the mitochondrial K(ATP) channel, which has been shown to be involved in cardioprotection. Estrogen can also activate rapid non-genomic pathways that activate cardioprotective-signaling pathways such as the phosphatidylinositol-3-kinase (PI-3 kinase) pathway which has also been shown to initiate protection. Taken together, estrogen by genomic and non-genomic pathways can result in the initiation of a number of signaling pathways that enhance cardioprotection.
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PMID:Cardioprotection in females: a role for nitric oxide and altered gene expression. 1750 81


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