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

From conventional relative gene expression analyses (Northern blotting, in situ hybridization, and RT-PCR), it has been reported that the expression of control genes, such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-actin, used as references may be affected by ischemia. Therefore, we extended searching and evaluation at the mRNA level of transcripts whose expression levels were not changed by cerebral ischemia, using a high-density oligonucleotide array and statistical analysis in a rat global cerebral ischemia and reperfusion model. We added a hyperthermic factor and localization factor to ischemia and identified transcripts with a stable expression level under conditions even more disadvantageous than ischemia only. Screening of more than 8,000 transcripts with the Rat Genome U34A array yielded 28 transcripts, which we listed and classified according to their expression level. Widely used control genes, GAPDH and beta-actin, were not included, although cyclophilin A was included. In addition, we conducted a functional classification based on gene ontology. Under the functional classification of the 28 transcripts, many genes tended to be associated with metabolism. In conclusion, use of several transcripts is recommended, such as those we identified, as references in the analysis of gene expression in pathological models of ischemia.
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PMID:Screening for control genes in rat global cerebral ischemia using high-density oligonucleotide array. 1511 23

Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants and/or a depletion of antioxidants. A considerable body of recent evidence suggests that oxidant stress plays a major role in several aspects of acute and chronic inflammation and is the subject of this review. Immunohistochemical and biochemical evidence demonstrate the significant role of reactive oxygen species (ROS) in acute and chronic inflammation. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na+/K+ ATP-ase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of ROS. All these toxicities are likely to play a role in the pathophysiology of shock, inflammation and ischemia and reperfusion. (2) Treatment with either peroxynitrite decomposition catalysts, which selectively inhibit peroxynitrite, or with SODm's, which selectively mimic the catalytic activity of the human superoxide dismutase (SOD) enzymes, have been shown to prevent in vivo the delayed tissue injury and the cellular energetic failure associated with inflammation. ROS (e.g., superoxide, peroxynitrite, hydroxyl radical and hydrogen peroxide) are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Antioxidant treatment inhibits the activation of PARS, and prevents the organ injury associated with acute and chronic inflammation.
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PMID:Potential therapeutic effect of antioxidant therapy in shock and inflammation. 1513 12

Because we were interested in assessing glucose-mediated regulation of the activity of sarcolemmal ATP-sensitive K(+) channels (K(ATP) channels) (which are closed by physiological levels of intracellular ATP and serve to couple intracellular metabolism with the membrane excitability in the heart) during ischemia, we performed experiments designed to test whether high extracellular glucose would have effects on sarcolemmal K(ATP) channels per se. Surprisingly, we found that high extracellular glucose (50 mmol/l) activates sarcolemmal K(ATP) channels in isolated guinea pig cardiomyocytes. To activate K(ATP) channels, glucose had to be transported into cardiomyocytes and subjected to glycolysis. The activation of these channels was independent of ATP production and intracellular ATP levels. The effect of glucose on sarcolemmal K(ATP) channels was mediated by the catalytic activity of glyceraldehyde-3-phosphate dehydrogenase and consequent generation of 1,3-bisphosphoglycerate. The 1,3-bisphosphoglycerate (20 mmol/l), an intermediate product of glycolysis, directly targeted and activated K(ATP) channels, despite physiological levels of intracellular ATP (5 mmol/l). We conclude that glucose, so far exclusively viewed as a metabolic fuel in the heart important only during ischemia/hypoxia, may serve a signaling role in the nonstressed myocardium by producing an agent that regulates cardiac membrane excitability independently of high-energy phosphates.
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PMID:High glucose regulates the activity of cardiac sarcolemmal ATP-sensitive K+ channels via 1,3-bisphosphoglycerate: a novel link between cardiac membrane excitability and glucose metabolism. 1567 96

In conventional relative gene expression analysis (Northern blotting, RT-PCR, and in situ hybridization), housekeeping genes such as the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-actin genes, whose expression levels are considered stable, have been used as control genes for normalization of RNA quantitation. However, it has been reported that the expression levels of these two control genes are affected by ischemia. Therefore, we have been searching for novel control genes whose expression levels are stable in a mouse model of transient forebrain ischemia. Using the GeneChip Mu6500 array set, we monitored the expression levels of approximately 6000 murine genes in the mouse hippocampus during 24 h of ischemia-reperfusion. To select stable genes, we applied the restricted criterion of a 1.5-fold change in expression level as the threshold. By adding statistical analysis with this criterion, we identified 10 genes as candidates for control genes from the GeneChip data. In this criterion, GAPDH and beta-actin genes were not included in the 10 genes as candidates for control genes. The present findings might be relevant to the use of control genes in quantitation of RNA, particularly in the study of mouse transient forebrain ischemia.
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PMID:Screening for control genes in mouse hippocampus after transient forebrain ischemia using high-density oligonucleotide array. 1671

Infarct size is a good predictor of the neurological outcome following stroke. Estimation of infarct size in the early phase following experimental stroke depends on the availability of reliable techniques that can distinguish ischemic from nonischemic tissue. The objective of this study was to provide a simple and robust method for reliable delineation of the ischemic infarct area in fresh frozen cryosections from mice subjected to focal cerebral ischemia. Mice were subjected to permanent middle cerebral artery (MCA) occlusion and euthanised after 30 min, 1, 2, 4, 6, 12 and 24 h. The size of the developing infarct was compared in parallel series of sections in situ hybridized for mRNA encoding the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or stained with toluidine blue (TB). The infarct was clearly delineated in GAPDH mRNA in situ hybridized sections as soon as 4 h after MCA occlusion. Infarct size was similar at 4 and 6 h in GAPDH mRNA in situ hybridized sections. Sections hybridized for GAPDH mRNA showed significantly larger infarcts than sections stained with TB after 6 h but not after 24 h of ischemia. Analysis of in situ hybridized sections revealed changes in neuronal GAPDH mRNA in areas prone to undergo degeneration 30 min to 1 h after MCA occlusion, thereby preceding visible pycnosis in TB-stained sections. The results showed that in situ hybridization for GAPDH mRNA was a reliable method and superior to TB staining for precise infarct delineation prior to 6 h of permanent MCA occlusion.
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PMID:Glyceraldehyde-3-phosphate dehydrogenase versus toluidine blue as a marker for infarct volume estimation following permanent middle cerebral artery occlusion in mice. 1672 6

In addition to their role in physiological activities, ionotropic glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) play an important role in neuronal death, especially that following ischemic insults. In this study, we examined the effect of single (SI) and twice repeated (RI)-4-vessel occlusion-ischemia on rat performance in the 8-armed radial maze test. Moreover, the effects of SI and RI on the AMPARs subunits glutamate receptor (GluR) 1 and GluR2 flip and flop variants composition in the CA1 subregion of the hippocampus were investigated using RT-PCR, normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and expressed as their ratios to the latter. The results showed that SI and RI impaired the maze performance by decreasing correct choices and increasing the error choices, but RI increased error choices to a greater extent than the SI. The SI reduced only GluR1 flip/GAPDH on day 1. The SI did not alter ratios of GluR2 variants to those of GluR1. On the other hand, the RI decreased GluR2 flip and flop variants after 1 and 3 days, respectively, whereas after 7 days, it increased the flip variant of both GluR1 and GluR2. Moreover, the RI reduced ratios of GluR2 variants to those of GluR1. These results reveal the differential effects of the SI and RI on memory and expression of the AMPARs subunits GluR1 and GluR2 and their flip and flop variants in the CA1.
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PMID:Comparison of single- and repeated-ischemia-induced changes in expression of flip and flop splice variants of AMPA receptor subtypes GluR1 and GluR2 in the rats hippocampus CA1 subregion. 1725 88

A major complication of aneurysmal subarachnoid hemorrhage (SAH) is symptomatic vasospasm, a complex syndrome consisting of neurological deterioration and exclusion of other sources of ischemia. Approximately 30% of SAH patients are affected. Although symptomatic vasospasm is associated with high mortality and poor clinical outcome, it is not possible to identify the individual risk on a molecular level for patients before symptoms have developed. In this study, we hypothesize that protein changes occur in the cerebral microdialysate of patients who later develop symptomatic vasospasm which are not found in matched-pairs control subjects. We searched for changes in protein concentrations in microdialysate sampled from the fronto-temporal brain tissue of five vasospastic and five nonvasospastic SAH patients using proteomics technology based on two-dimensional gel electrophoresis and mass spectrometry. Microdialysate samples were taken at least 1.5 days before the onset of symptomatic vasospasm. Comparing protein expression profiles, we found that the protein concentrations of several isoforms of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were 1.79-fold+/-1.29 (N=5, P<0.05) higher in the group which later developed symptomatic vasospasm, whereas heat-shock cognate 71 kDa protein (HSP7C) isoforms were decreased to 0.50-fold+/-0.19 (N=5, P<0.05; all expression data means+/-s.d.). The changes in protein concentrations were detected 3.8+/-1.7 days (N=5, P<0.05) before symptomatic vasospasm developed. We conclude that GAPDH and HSP7C may be used as early markers indicating the later development of symptomatic vasospasm after SAH, enabling selective early therapeutic intervention in this high-risk group of patients.
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PMID:Identification of early markers for symptomatic vasospasm in human cerebral microdialysate after subarachnoid hemorrhage: preliminary results of a proteome-wide screening. 1732 82

Oxidative stress is a major pathogenic event occurring in several brain disorders and is a major cause of brain damage due to ischemia/reperfusion. Thiol proteins are easily oxidized in cells exposed to reactive oxygen species (ROS). In the present study, we investigated transient ischemia-induced chronological changes in hyperoxidized peroxiredoxins (Prx-SO3) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH-SO3) immunoreactivity and protein levels in the gerbil hippocampus induced by 5 min of transient forebrain ischemia. Weak Prx-SO3 immunoreactivity is detected in the hippocampal CA1 region of the sham-operated group. Prx-SO3 immunoreactivity was significantly increased 12 h and 1 day after ischemia/reperfusion, and the immunoreactivity was decreased to the level of the sham-operated group 2 days after ischemia/reperfusion. Prx-SO3 immunoreactivity in the 4 days post-ischemia group was increased again, and the immunoreactivity was expressed in glial components for 5 days after ischemia/reperfusion. GAPDH-SO3 immunoreactivity was highest in the CA1 region 1 day after ischemia/reperfusion, the immunoreactivity was decreased 2 days after ischemia/reperfusion. Four days after ischemia/reperfusion, GAPDH-SO3 immunoreactivity increased again, and the immunoreactivity began to be expressed in glial components from 5 days after ischemia/reperfusion. Prx-SO3 and GAPDH-SO3 protein levels in the ischemic CA1 region were also very high 12 h and 1 day after ischemia/reperfusion and returned to the level of the sham-operated group 3 days after ischemia/reperfusion. Their protein levels were increased again 5 days after ischemia/reperfusion. In conclusion, Prx-SO3 and GAPDH-SO3 immunoreactivity and protein levels in the gerbil hippocampal CA1 region are significantly increased 12 h-24 h after ischemia/reperfusion and their immunoreactivity begins to be expressed in glial components from 4 or 5 days after ischemia/reperfusion.
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PMID:Hyperoxidized peroxiredoxins and glyceraldehyde-3-phosphate dehydrogenase immunoreactivity and protein levels are changed in the gerbil hippocampal CA1 region after transient forebrain ischemia. 1745 73

In bladder outlet obstruction (BOO), mechanical stress and ischemia/hypoxia are implicated in structural and functional alterations of the urinary bladder. Because mechanical stress and hypoxia may trigger endoplasmic reticulum (ER) stress, we examined involvement of ER stress in the damage of the bladder caused by BOO. An experimental model of BOO was established in rats by complete ligature of the urethra for 24 h, and bladders were subjected to northern blot analysis and assessment of apoptosis. Isolated urinary bladders and bladder-derived smooth muscle cells (BSMCs) were also exposed to mechanical strain and hypoxia and used for analyses. To examine involvement of ER stress in the damage of the bladder, the effects of a chemical chaperone 4-phenylbutyrate (4-PBA) were evaluated in vitro and in vivo. Outlet obstruction for 24 h induced expression of ER stress markers, GRP78 and CCAAT/enhancer-binding protein-homologous protein (CHOP), in the bladder. It was associated with induction of markers for mechanical stress (cyclooxygenases 2) and hypoxia (vascular endothelial growth factor and glyceraldehyde-3-phosphate dehydrogenase). When isolated bladders and BSMCs were subjected to mechanical strain, induction of GRP78 and CHOP was not observed. In contrast, when BSMCs were exposed to hypoxic stress caused by CoCl2 or thenoyltrifluoroacetone (TTFA), substantial upregulation of GRP78 and CHOP was observed, suggesting involvement of hypoxia in the induction of ER stress. In the bladder subjected to BOO, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells increased in the epithelial cells and BSMCs. Similarly, treatment with TTFA or CoCl2 induced apoptosis of BSMCs, and 4-PBA significantly attenuated ER stress and apoptosis triggered by these agents. Furthermore, in vivo administration with 4-PBA significantly reduced apoptosis in the bladder subjected to BOO. These results suggested that outlet obstruction caused ER stress via hypoxic stress in the bladder and that hypoxia-triggered ER stress may be involved in the induction of apoptosis in BOO.
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PMID:Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder. 1834 81

After ischemic renal injury (IRI), selective damage occurs in the S(3) segments of the proximal tubules as a result of inhibition of glycolysis, but the mechanism of this inhibition is unknown. We previously reported that inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) activity protects against ischemia-induced necrosis in proximal tubules by preserving ATP levels. Here, we tested whether PARP-1 activation in proximal tubules after IRI leads to poly(ADP-ribosyl)ation of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a modification that inhibits its activity. Using in vitro and in vivo models, under hypoxic conditions, we detected poly(ADP-ribosyl)ation and reduced activity of GAPDH; inhibition of PARP-1 activity restored GAPDH activity and ATP levels. Inhibition of GAPDH with iodoacetate exacerbated ATP depletion, cytotoxicity, and necrotic cell death of LLCPK(1) cells subjected to hypoxic conditions, whereas inhibition of PARP-1 activity was cytoprotective. In conclusion, these data indicate that poly(ADP-ribosyl)ation of GAPDH and the subsequent inhibition of anaerobic respiration exacerbate ATP depletion selectively in the proximal tubule after IRI.
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PMID:PARP-1 inhibits glycolysis in ischemic kidneys. 1905 68


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