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)

Expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a potent angiogenic factor, is upregulated in response to a hypoxic or hypoglycemic stress. Here we show that the increase in steady-state levels of VEGF mRNA is partly due to transcriptional activation but mostly due to increase in mRNA stability. Both oxygen and glucose deficiencies result in extension of the VEGF mRNA half-life in a protein synthesis-dependent manner. Viewing VEGF as a stress-induced gene, we compared its mode of regulation with that of other stress-induced genes. Results showed that under nonstressed conditions, VEGF shares with the glucose transporter GLUT-1 a relatively short half-life (0.64 and 0.52 h, respectively), which is extended fourfold and more than eightfold, respectively, when cells are deprived of either oxygen or glucose. In contrast, the mRNAs of another hypoxia-inducible and hypoglycemia-inducible gene, grp78, as well as that of HSP70, were not stabilized by these metabolic insults. To show that VEGF and GLUT-1 are coinduced in differentially stressed microenvironments, multicell spheroids representing a clonal population of glioma cells in which each cell layer is differentially stressed were analyzed by in situ hybridization. Cellular microenvironments conducive to induction of VEGF and GLUT-1 were completely coincidental. These findings show that two different consequences of tissue ischemia, namely, hypoxia and glucose deprivation, induce VEGF and GLUT-1 expression by similar mechanisms. These proteins function, in turn, to satisfy the tissue needs through expanding its vasculature and improving its glucose utilization, respectively.
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PMID:Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes. 756 86

The present study examined the immunocytochemical expression of the blood-brain barrier glucose transporter (GLUT-1) in a series of fetal neocortical transplants, autonomic tissue transplants, and stab wounds to the rat brain. GLUT-1 is one of a family of different glucose transporters and is found exclusively on barrier-type endothelial cells. In the brain it is responsible for the regulated facilitative diffusion of glucose across the blood-brain barrier. This investigation is the first to determine if this important molecule is altered during the process of angiogenesis that occurs following neural transplantation procedures or direct brain injury. Beginning in late fetal brain, e.g., E18 and continuing into maturity, GLUT-1 was strongly and exclusively expressed on normal cerebral vessels. In solid fetal central nervous system (CNS) transplants up to around 3 weeks postoperative, GLUT-1 was only weakly expressed, particularly as exemplified by colloidal gold immunostaining when compared with the host. At later times examined, up to 15 months postoperative, GLUT-1 immunoexpression was comparable with the normal adjacent brain. In autonomic tissue transplants, where the vessels do not have a blood-brain barrier, as expected, GLUT-1 was not expressed. In stab wounds, at 1 week there was extensive gliosis, and the injured vessels appeared fragmented and collapsed but still expressed GLUT-1, although to a somewhat lesser extent than normal brain. Between 3 and 6 weeks, GLUT-1 was expressed on tortuous vessels and in apparently fibrillar processes in the wound vicinity with a similar pattern to astrocyte (GFAP) reactivity. These results suggest the occurrence of a down-regulation of GLUT-1 in early transplants, perhaps related to reduced glycolytic activity or transient ischemia, or possibly due to the utilization of alternative energy sources. That GLUT-1 expression was not entirely lost in stab wounds to the mature brain suggests that the protein may be more labile in fetal or perinatal brain than in the adult and may not be affected by direct injury. Coupled with previous transplantation studies that have shown reduced neuronal glycolysis and potential barrier alterations, the reduction of GLUT-1 activity within nearly the identical time frame could indicate a relatively early critical period in cellular metabolism following transplantation of CNS tissue.
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PMID:Immunocytochemical expression of the blood-brain barrier glucose transporter (GLUT-1) in neural transplants and brain wounds. 788 40

Glucose transport into nonneuronal brain cells uses differently glycosylated forms of the glucose transport protein, GLUT1. Microvascular GLUT1 is readily seen on immunocytochemistry, although its parenchymal localization has been difficult. Following ischemia, GLUT1 mRNA increases, but whether GLUT1 protein also changes is uncertain. Therefore, we examined the immunocytochemical distribution of GLUT1 in normal rat brain and after transient global forebrain ischemia. A novel immunocytochemical finding was peptide-inhibitable GLUT1 immunoreactive staining in parenchyma as well as in cerebral microvessels. In nonischemic rats, parenchymal GLUT1 staining co-localizes with glial fibrillary acidic protein (GFAP) in perivascular foot processes of astrocytes. By 24 h after ischemia, both microvascular and nonmicrovascular GLUT1 immunoreactivity increased widely, persisting at 4 days postischemia. Vascularity within sections of brain similarly increased after ischemia. Increased parenchymal GLUT1 expression was paralleled by staining for GFAP, suggesting that nonvascular GLUT1 overexpression may occur in reactive astrocytes. A final observation was a rapid expression of inducible heat shock protein (HSP)70 in hippocampus and cortex by 24 h after ischemia. We conclude that GLUT1 is normally immunocytochemically detectable in cerebral microvessels and parenchyma and that parenchymal expression occurs in some astroglia. After global cerebral ischemia, GLUT1 overexpression occurs rapidly and widely in microvessels and parenchyma; its overexpression may be related to an immediate early-gene form of response to cellular stress.
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PMID:Forebrain ischemia increases GLUT1 protein in brain microvessels and parenchyma. 853 May 57

A number of observations indicate that myocardial glucose utilization is increased late during post-ischemic reperfusion. The present study was designed to examine whether transient ischemia elicits altered expression of glucose transporters GLUT-1 and GLUT-4. In rats, the left anterior descending coronary artery was occluded for 20 min followed by reperfusion for 1, 3 or 7 days. Regional myocardial uptake and phosphorylation of glucose was determined based on myocardial accumulation of 2-deoxy-D-[2, 6-3H]glucose-6-phosphate. In hearts from fasted rats, after 3 days of reperfusion, myocardial uptake and phosphorylation of glucose was 48% higher in the reperfused region compared to a remote control region. No regional difference in myocardial glucose uptake and phosphorylation was detectable in hearts from fed rats. After 1 day of reperfusion, expression of myocardial glucose transporter GLUT-1 mRNA was increased to 195+/-24% (mean+/-SEM) of the value measured in the remote region and the expression of GLUT-4 mRNA was decreased to 58+/-7%. After 3 days of reperfusion both mRNA and protein of GLUT-1 were higher in the reperfused region, averaging 133+/-23% and 249+/-36%, respectively. The corresponding values for GLUT-4 mRNA and protein were 77+/-7% and 62+/-6%, respectively. The results indicate that a short period of ischemia alters the expression of glucose transporter isoforms GLUT-1 and GLUT-4. Observed changes may be involved in the mechanisms underlying late changes of substrate metabolism during reperfusion.
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PMID:Effect of transient ischemia on the expression of glucose transporters GLUT-1 and GLUT-4 in rat myocardium. 1033 52

Neovascularization in the adult central nervous system occurs as a response to several pathophysiological conditions such as ischemia, wound repair, or neoplasia. Endothelial cells from different blood vessel types, different organs, and different species are heterogeneous; therefore, the appropriate cell type should be used to study specific aspects of vascular pathology. We have developed a method to isolate human cerebral microvascular endothelial cells (CMECs) from small, freshly obtained specimens of normal brain adherent to human arteriovenous malformations (AVMs). The isolation procedure involves enzymatic digestions and gradient centrifugations, yielding over 95% pure primary cultures. Alternative isolation methods using magnetic beads, panning, or cloning were not superior with regard to cell purity or yield. CMECs were identified by their immunoreactivity for vWF, CD34, EN4, binding of Ulex europeus lectin, and uptake of DiI-Ac-LDL. They displayed ultrastructural features characteristic of blood-brain barrier endothelial cells and expressed GLUT-1. CMECs were subcultured; however, prolonged culture led to reduced culture purity. Vascular endothelial growth factor, basic fibroblast growth factor and hepatocyte growth factor/scatter factor stimulated the directional motility of CMECs, with dose-response profiles similar to human umbilical vein endothelial cells (HUVECs). In contrast, to stimulate proliferation, lower concentrations of growth factors tended to be necessary for CMECs than for the large vessel endothelial cells. CMECs formed capillary tube-like structures in an in vitro angiogenesis assay using matrigel. This study expands the spectrum of available tissue sources for the isolation of human neuromicrovascular endothelial cells, which are essential for the in vitro study of blood-brain barrier function and cerebral angiogenesis.
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PMID:Isolation and culture of human neuromicrovascular endothelial cells for the study of angiogenesis in vitro. 1034 68

Metabolic interventions that promote glucose use during ischemia have been shown to protect ischemic myocardium and improve functional recovery on reperfusion. We evaluated whether the cardioprotection afforded by high glucose during low-flow ischemia is associated with changes in the sarcolemmal content of glucose transporters, specifically GLUT-4. Isolated rat hearts were paced at 300 beats/min and perfused under normal glucose (5 mM) or high glucose (10 mM) conditions in buffer containing 0.4 mM albumin, 0.4 mM palmitate, and 70 mU/l insulin and subjected to 50 min of low-flow ischemia and 60 min of reperfusion. To determine the importance of insulin-sensitive glucose transporters in mediating cardioprotection, a separate group of hearts were perfused in the presence of cytochalasin B (10 microM), a preferential inhibitor of insulin-sensitive glucose transporters. Ischemic contracture during low-flow ischemia and creatine kinase release on reperfusion was decreased, and the percent recovery of left ventricular function with reperfusion was enhanced in hearts perfused with high glucose (P < 0.03). Hearts perfused with high glucose exhibited increased GLUT-4 protein expression in the sarcolemmal membrane compared with control hearts under baseline conditions, and these changes were additive with low-flow ischemia. In addition, high glucose did not affect the baseline distribution of sarcolemmal GLUT-1 and blunted any changes with low-flow ischemia. These salutary effects were abolished when glucose transporters are blocked with cytochalasin B. These data demonstrate that protection of ischemic myocardium by high glucose is associated with increased sarcolemmal content of the insulin-sensitive GLUT-4 and suggest a target for the protection of jeopardized myocardium.
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PMID:Protection of ischemic hearts by high glucose is mediated, in part, by GLUT-4. 1140 96

ATP and creatine phosphate (PCr) are prime myocardial high-energy phosphates. Their relative concentrations are conserved among mammalian species and across a range of physiologic cardiac workloads. The cardiac PCr/ATP ratio is decreased with several pathologic conditions, such as ischemia and heart failure, but there are no reports of an increase in the cardiac PCr/ATP ratio in any species or with interventions. We studied the in vivo energetics in transgenic mice lacking expression of the glucose transport protein GLUT4 (G4N) and observed a significant 60% increase in the myocardial PCr/ATP ratio in G4N that was confirmed in three different experimental settings including intact animals. The higher PCr/ATP in G4N is cardiac-specific and is due to higher total cardiac creatine (CR) concentrations in G4N than in wild-type (WT). However, [ATP], [ADP], and -DG(-ATP) did not differ between the strains. Expression of the creatine transport protein (CreaT) that is responsible for creatine uptake in myocytes was preserved in G4N cardiac tissue. These observations demonstrate, for the first time to our knowledge, that G4N manifest a unique increase in the cardiac PCr/ATP ratio, which suggests a novel genetic strategy for increasing myocardial creatine levels.
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PMID:An increase in the myocardial PCr/ATP ratio in GLUT4 null mice. 1191 71

Hypoxic preconditioning (8% O2, 3 h) produces tolerance 24 h after hypoxic-ischemic brain injury in neonatal rats. To better understand the ischemic tolerance mechanisms induced by hypoxia, we used oligonucleotide microarrays to examine genomic responses in neonatal rat brain following 3 h of hypoxia (8% O2) and either 0, 6, 18, or 24 h of re-oxygenation. The results showed that hypoxia-inducible factor (HIF)-1- but not HIF-2-mediated gene expression may be involved in brain hypoxia-induced tolerance. Among the genes regulated by hypoxia, 12 genes were confirmed by real time reverse transcriptase-PCR as follows: VEGF, EPO, GLUT-1, adrenomedullin, propyl 4-hydroxylase alpha, MT-1, MKP-1, CELF, 12-lipoxygenase, t-PA, CAR-1, and an expressed sequence tag. Some genes, for example GLUT-1, MT-1, CELF, MKP-1, and t-PA did not show any hypoxic regulation in either astrocytes or neurons, suggesting that other cells are responsible for the up-regulation of these genes in the hypoxic brain. These genes were expressed in normal and hypoxic brain, heart, kidney, liver, and lung, with adrenomedullin, MT-1, and VEGF being prominently induced in brain by hypoxia. These results suggest that a number of endogenous molecular mechanisms may explain how hypoxic preconditioning protects against subsequent ischemia, and may provide novel therapeutic targets for treatment of cerebral ischemia.
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PMID:Brain genomic response following hypoxia and re-oxygenation in the neonatal rat. Identification of genes that might contribute to hypoxia-induced ischemic tolerance. 1214 88

The high energy demands of myocardium are met through the metabolism of lipids and glucose. Importantly, enhanced glucose utilization rates are crucial adaptations of the cardiac cell to some pathological conditions, such as hypertrophy and ischemia, but the effects of undernutrition on heart glucose metabolism are unknown. Our previous studies have shown that undernutrition increases insulin-induced glucose uptake by skeletal muscle. Consequently, we considered the possibility of a similar adaptation in the heart. With this aim, undernourished rats both in the basal state and after euglycemic hyperinsulinemic clamps were used to determine the following parameters in myocardium: glucose uptake, glucose transporter (GLUT) content, and some key components of the insulin signaling cascade. Heart membranes were prepared by subcellular fractionation in sucrose gradients. Although GLUT-4, GLUT-1, and GLUT-3 proteins and GLUT-4/1 mRNAs were reduced by undernutrition, basal and insulin-stimulated 2-deoxyglucose uptake were significantly enhanced. Phosphoinositol 3-kinase activity remained greater than control values in both conditions. The abundance of p85alpha and p85beta regulatory subunits of phosphoinositol 3-kinase was increased as was phospho-Akt during hyperinsulinemia. These changes seem to improve the insulin stimulus of GLUT-1 translocation, as its content was increased at the surface membrane. Such adaptations associated with undernutrition must be crucial to improvement of cardiac glucose uptake.
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PMID:Effects of chronic undernutrition on glucose uptake and glucose transporter proteins in rat heart. 1239 25

We examined the effect of hypoxic ischemia and hypoxia vs. normoxia on postnatal murine brain substrate transporter concentrations and function. We detected a transient increase in the neuronal brain glucose transporter isoform (GLUT-3) in response to hypoxic ischemia after 4 h of reoxygenation. This increase was associated with no change in GLUT-1 (blood-brain barrier/glial isoform), monocarboxylate transporter isoforms 1 and 2, synapsin I (neuronal marker), or Bax (proapoptotic protein) but with a modest increase in Bcl-2 (antiapoptotic mitochondrial protein) protein concentrations. At 24 h of reoxygenation, the increase in GLUT-3 disappeared but was associated with a decline in Bcl-2 protein concentrations and the Bcl2:Bax ratio, an increase in caspase-3 enzyme activity (apoptotic effector enzyme), and extensive DNA fragmentation, which persisted later in time (48 h) only in the hippocampus. Hypoxia alone in the absence of ischemia was associated with a transient but modest increase in GLUT-3 and synapsin I protein concentrations, which did not cause significant apoptosis and/or necrosis. Assessment of glucose transporter function by 2-deoxyglucose (2-DG) uptake using two distinct techniques, namely positron emission tomography (PET) and the modified Sokoloff method, revealed a discrepancy due to glucose uptake by extracranial Harderian glands that masked the accurate detection of intracranial brain glucose uptake by PET scanning. The modified Sokoloff method assessing 2-DG uptake revealed that the transient increase in GLUT-3 was critical in protecting against a decline in brain glucose uptake. We conclude that hypoxic-ischemic brain injury is associated with transient compensatory changes targeted at protecting glucose delivery to fuel cellular energy metabolism, which then may delay the processes of apoptosis and cell necrosis.
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PMID:Postnatal hypoxic-ischemic brain injury alters mechanisms mediating neuronal glucose transport. 1452 22


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