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)

Resistance to O2 diffusion is reflected in the difference in pO2 between O2 reservoirs of hemoglobin (Hb) and myoglobin. The very low normal myocyte pO2 (less than one torr but adequate for optimal oxidative ATP synthesis) compared to venous pO2 indicates that blood does not achieve equilibrium with tissue during its passage through capillaries. In the lung, diffusion rate of O2 from alveolus to capillary is normally sufficient to achieve essential equilibrium. However, system-wide capillary pathology and reduced Hb saturation has been observed with distal local ischemia. In peripheral vascular disease (PVD) patients, we found a mean arterial pO2 of 77 torr (normal over 90 torr). Classical concepts based on "tissue pO2" values derived from venous blood or oxygen electrodes inserted into tissue need re-evaluation. Readings of O2 electrodes moved through tissue range widely from intracapillary levels down toward intracellular levels and do not reflect the pO2 of any particular site. Intravenous pO2 is the result of residual O2 after incomplete diffusion out of capillaries during transit through a tissue, and is not an equilibrium value with some tissue pool. The effect of HbO2 p50 on oxygen release during the passage of blood through a capillary bed, generally judged on the basis of percentage percent saturation at "tissue pO2", should be judged on the basis of the change in pO2 (the diffusion driving force) associated with a particular degree of HbO2 saturation at a particular p50. The thesis that O2 diffusion rate is a major determinant of oxygen delivery is supported by pO2 responses to treatment of PVD that does not alter blood flow or p50.
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PMID:Concepts of "tissue PO2" in relation to O2 delivery. 799 99

Hypoxia and reoxygenation are important pathophysiological conditions that occur during injury, ischemia, reperfusion and stroke. In tumors, hypoxia and oxidative stress are regarded as triggers for enhanced proliferation and metastasis. Hypoxia and reoxygenation exert part of their biological effects by inducing the expression of novel genes but very little is known about the transcription factors involved. Here, we have compared the behaviour of two redox-controlled factors, AP-1 and NF-kappa B, during hypoxia and reoxygenation. We report that the DNA-binding and transcriptional activity of transcription factor AP-1 is very strongly induced in a biphasic response when HeLa cells are exposed to reduced oxygen pressure. This induction required new AP-1 protein synthesis. Different members of the Jun/Fos family of transcription factors were found in the first and second maxima of activation. The pathogen-responsive, pre-existing transcription factor NF-kappa B was not activated under hypoxic conditions. However, a p50-p65 heterodimer of NF-kappa B was rapidly and strongly activated when HeLa cells were re-exposed to normal oxygen pressure. This explains the induction of NF-kappa B-controlled inflammatory cytokine genes during reperfusion of ischemic tissue. Our data suggest that the genomic response to hypoxia is primarily mediated by AP-1 while the inflammatory response to reoxygenation is mediated by NF-kappa B.
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PMID:The genomic response of tumor cells to hypoxia and reoxygenation. Differential activation of transcription factors AP-1 and NF-kappa B. 853 13

Ischemia/reperfusion induces nuclear factor kappaB (NF-kappaB) and AP-1 in rat hearts after 15 min of ischemia followed by reperfusion (R) for various periods of time (15 and 30 min, 1, 2, 3, 6, 12, and 24 h). Low levels of NF-kappaB and no signal for AP-1 were detected in shams and in non-ischemic tissue distant from the ischemic zone. In postischemic tissue, NF-kappaB levels increased biphasically with peak levels at 15 min and again at 3 h R. Immunoblotting showed minimal NF-kappaB p50 subunit at all times, with changes in p65 similar to EMSA results. Northern blots showed low p50 and increased p65 expression levels at both 2 and 3 h R. By contrast, AP-1 increased monophasically, with peak levels at 15 min R, which dropped steadily thereafter. These results indicate that NF-kappaB and AP-1 are differentially regulated during reperfusion, which may be a control mechanism for gene expression in reperfused myocardium.
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PMID:Induction of nuclear factor kappaB and activation protein 1 in postischemic myocardium. 900

The aim of this study was to investigate the behavior of the transcription factors, heat-shock factor (HSF) and nuclear factor kappaB (NF-kappaB), in postischemic reperfused liver, with particular attention paid to possible differences in the time-course and mechanism of activation, which may help in defining their role in the response of the liver to reperfusion. Ischemia was induced by clamping the hilar pedicle of the left lateral and median liver lobes; the clamp was removed after 1 hour. Some rats were treated intraperitoneally with IL-1 receptor antagonist (IL-1RA) 30 minutes before ischemia and at the time of reperfusion. Binding of NF-kappaB to the corresponding consensus sequence is activated after 30 minutes of reperfusion, and is still increased 1 hour after reperfusion. Activation is suppressed in rats treated with IL-1RA; NF-kappaB persists in the cytosol associated with the inhibitor, IkappaB, and can be artifactually activated in vitro. Super-gel shift experiments revealed that the two subunits, p50 and p65, are involved in the activation of binding. In contrast, binding of HSF to the corresponding consensus sequence, heat shock element (HSE), is already activated at the end of ischemia, shows a further increase after 30 minutes of reperfusion, but declines 1 hour after reperfusion; more importantly, it is not inhibited by pretreatment of the rat with IL-1RA. In conclusion, although both HSF and NF-kappaB are activated by ischemia-reperfusion, there are clear differences in time-course and mechanism of activation of the two transcription factors. Activation of HSF depends directly on some events occurring during ischemia; NF-kappaB is activated only after reperfusion and the concurrent oxidative stress, by an indirect mechanism that can be suppressed by IL-1RA. The possibility of dissociating the activation of these two transcription factors in postischemic reperfusion can have a prospective clinical relevance.
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PMID:Differential activation of heat shock and nuclear factor kappaB transcription factors in postischemic reperfused rat liver. 921 68

The oxidative stress responsive transcription factor nuclear factor-kappa B (NF-kappa B) consists of a p50 (50 kDa) and p65/RelA (65 kDa) component and can be activated in vitro by TNF alpha, IL1 beta, hydrogen peroxide and oxygen radicals. All of the above factors are also known to be elevated at certain times after transient global ischemia. The present study was performed to determine if NF-kappa B was activated in vivo by transient global forebrain ischemia. Adult male rats were subjected to 30 min of 4-vessel occlusion (4-VO) and sacrificed at selected post-ischemic time points. Levels of NF-kappa B p50 and p65 subunits were determined by immunocytochemistry, Western blot and electrophoretic mobility-shift analysis. The enhancer complex was also confirmed by immuno-gel-shift analysis. Specific labeling of DNA strand breaks and DNA fragmentation was examined in situ by means of the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method. Western blot analysis of hippocampus showed induction of p50 and p65. A time course of NF-kappa B induction in hippocampus showed a p50-specific band at 6 h that increased in intensity over 12, 48 h and then decreased by 96 h post-ischemia. Immunocytochemistry revealed at 24 h post-ischemia that p65 and p50 immunoreactivity was present in neuronal nuclei of hippocampal CA1 neurons as well as all other hippocampal regions and several other forebrain regions which were not vulnerable to transient forebrain ischemia. At 72 h post-ischemia, nuclear NF-kappa B immunoreactivity had disappeared in all brain areas except in hippocampal CA1 neurons which were degenerating. No evidence for DNA fragmentation as revealed by TUNEL staining could be observed at 24 h. However, at 72 h, hippocampal CA1 neurons were heavily labeled. The results of this study demonstrate that global forebrain ischemia causes a transient activation of NF-kappa B in many forebrain regions. NF-kappa B remains persistently activated in the vulnerable hippocampal CA1 sector. Because of the persistent activation of NF-kappa B in these neurons, the possibility exists that NF-kappa B has a role in programmed cell death in hippocampal CA1 neurons.
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PMID:Global cerebral ischemia activates nuclear factor-kappa B prior to evidence of DNA fragmentation. 933 15

Reduced brain tissue oxygenation is frequently seen in severe head injury and after subarachnoid hemorrhage, and this is considered a major cause of secondary ischemic brain injury. In fact, in a previous study, we found a tight correlation between low brain tissue oxygen tension and poor outcome. Therefore, we tested the hypothesis that an allosteric modifier of hemoglobin, which improves oxygen transport to tissue, could reduce the size of an acute infarct in a feline model of human stroke. This compound produces a shift in the hemoglobin dissociation curve to the right and therefore facilitates the unloading of oxygen during low oxygen tension. Seventeen adult cats were studied. Ischemic stroke was induced through a transorbital, permanent, middle cerebral artery occlusion. Seven animals received saline, and 10 received the allosteric Hb modifier RSR-13. Three different endpoints were used to determine the effect of the allosteric modifier. Delta p50 values were measured in the arterial blood; the intra-infarct oxygen tension was measured, and finally, the volume of the infarct was assessed using TTC staining. Mean delta p50 changes varied from 10.4 +/- 9.2 mmHg up to 15.0 +/- 6.8 mmHg. Mean intra-infarct oxygen tension was 27 +/- 6 mmHg for the control group and 33 +/- 7 mmHg for the drug-treated animals. The mean infarct size (measured as percentage of hemisphere volume) in the control group was 32 +/- 9% and for the RSR-13 animals 22 +/- 10% (p < 0.05). A definitive trend towards improvement in brain oxygen tension was seen, such that animals pretreated with RSR-13 showed a higher infarct oxygen tension. Infarct size was significantly reduced in the drug group. Therefore, RSR-13 is potentially beneficial in the treatment of brain ischemia. Since human studies with this compound are already completed, and other compounds which increase oxygen delivery, such as perfluorocarbons, are already being evaluated, it is likely that oxygen delivery enhancement will rapidly become the first 'neuroprotective' modality, employed in patients with severe brain injury, stroke and subarachnoid hemorrhage.
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PMID:The rationale for, and effects of oxygen delivery enhancement to ischemic brain in a feline model of human stroke. 936 91

Hippocampal CA1 neurons are highly susceptible to short periods of transient global ischemia. We have previously reported in a rat model of transient forebrain global ischemia that activation and nuclear localization of NF-kB occurs in the CA1 neurons at 24 and 72 h post reperfusion. Events following NF-kB activation would ultimately determine whether damaged cells will undergo programmed cell death. We have selected bcl-x gene expression for study because there is increasing evidence that proteins encoded by the bcl-2 gene family (bcl-2, bcl-x, bax etc) play a role in the regulation of programmed cell death. We have observed that the bcl-x gene promoter contains a putative consensus sequence for NF-kB/CS4 responsive activation. We also can show that other members of the bcl-2 multigene family contain the NF-kB/CS4 sequence in their five prime regulatory regions. In this study, we show that NF-kB p50 and NF-kB p65 act in synergy to transactivate the bcl-x promoter in co-transfected 293 cells. We also report that following ischemia and NF-kB activation, bcl-x messenger RNA levels increase in the CA1 hippocampal region. As a result of this transcriptional increase, surprisingly, it is bcl-xs, the apoptotic form of bcl-x, that is elevated. These results suggest that activation of NF-kB can lead to increased expression of bcl-x as manifested by the increase in the short form of bcl-x.
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PMID:Bcl-Xshort is elevated following severe global ischemia in rat brains. 943 16

Nuclear factor-kappaB (NF-kappaB) becomes activated under inflammatory conditions and triggers induction of gene expression. Here, activation of NF-kappaB was studied after transient middle cerebral artery occlusion in the rat. Expression of p65 and p50, protein subunits of NF-kappaB, was examined by Western blotting, and immunohistochemistry for p65 was carried out. Double-labelling with specific markers for astroglia and microglia was used for cell type identification. Neurons located within and surrounding the ischemic core were identified during the first 24 h post-ischemia by using an antibody against 72-kDa heat shock protein. NF-kappaB binding activity was evaluated at different times post-ischemia with electrophoretic mobility gel shift assays. The results showed constitutive expression of p65 and p50, and NF-kappaB binding activity. Basal p65 was seen in certain neurons and resting astrocytes. Constitutive NF-kappaB binding activity was attributable to one main protein complex possibly formed in neurons and astrocytes, although two minor complexes were also detected. At 1 day post-ischemia selective induction of p65 was seen in neurons located in a penumbra-like area. At this time, however, no disturbances of basal NF-kappaB binding activity were found. Western blotting showed delayed induction of p65 several days after ischemia, whereas no changes were detected for p50. From 4 days post-ischemia, a substantial increase in the amount of p65 was detected due to induction in reactive astrocytes and microglia/macrophages. This was correlated with a robust enhancement of NF-kappaB binding activity with formation of three major specific complexes binding DNA. It is proposed that the highly inducible NF-kappaB complexes resulted from induction of p65 and activation of NF-kappaB in post-ischemic reactive glia.
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PMID:Activation of nuclear factor-kappaB in the rat brain after transient focal ischemia. 1003 8

Conventional approaches for the treatment of myocardial ischemia increase coronary blood flow or reduce myocardial demand. To determine whether a rightward shift in the hemoglobin-oxygen saturation curve would reduce the metabolic and contractile effects of a myocardial oxygen-supply imbalance, we studied the impact of a potent synthetic allosteric modifier of hemoglobin-oxygen affinity, a 2-[4-[[(3,5-disubstituted anilino)carbonyl]methyl] phenoxy] -2-methylproprionic acid derivative (RSR13), during low-flow ischemia. Changes in myocardial high-energy phosphate levels and pH were studied by 31P nuclear magnetic resonance (NMR) spectroscopy in 12 open-chest dogs randomized to receive RSR13 or vehicle control during a reversible reduction of left anterior descending (LAD) coronary artery blood flow. Changes in cardiac metabolites and regional ventricular function studied by pressure segment-length relations were also investigated in additional animals before and after RSR13 administration during low-flow LAD ischemia. The intravenous administration of RSR13 before ischemia resulted in a substantial increase in the mean hemoglobin p50 and attenuated the decline in cardiac creatine phosphate/adenosine triphosphate (PCr/ATP), percent PCr, and pH during ischemia without a change in regional myocardial blood flow, heart rate, or systolic blood pressure. RSR13 given after the onset of low-flow ischemia also improved cardiac PCr/ATP ratios and regional function as measured by fractional shortening and regional work. Thus, synthetic allosteric reduction in hemoglobin-oxygen affinity may be a new and important therapeutic strategy to ameliorate the metabolic and functional consequences of cardiac ischemia.
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PMID:Preservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of hemoglobin-oxygen affinity. 1007 92

The transcription factor NF-kappaB is a regulator of cell death or survival. To investigate the role of NF-kappaB in neuronal cell death, we studied its activation in a rodent model of stroke. In the ischemic hemisphere, NF-kappaB was activated, as determined by increased expression of an NF-kappaB-driven reporter transgene, nuclear translocation of NF-kappaB in neurons and enhanced DNA binding of NF-kappaB subunits RelA and p50. In p50 knockout mice, ischemic damage was significantly reduced. This indicates a cell death-promoting role of NF-kappaB in focal ischemia. NF-kappaB may provide a new pharmacological target in neurologic disease.
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PMID:NF-kappaB is activated and promotes cell death in focal cerebral ischemia. 1022 33


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