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

Extracellular acidosis has been shown to be protective during ischemia in renal tubule cells. However, the mechanism of protection remains unknown. Since ischemia leads to disruption and polymerization of the cortical actin cytoskeleton, we hypothesized acidosis may better preserve the actin cytoskeleton during ischemia. Therefore, the purpose of our studies was to examine the effect of pH on the integrity of the actin cytoskeleton during ATP depletion and ATP repletion. To do this, we used an in vitro model of reversible ATP depletion in LLC-PK1 cells at extracellular pH values (pHo) of 6.9, 7.4, and 7.9. Immunofluorescent studies with rhodamine-phalloidin demonstrated more marked redistribution and clumping of cortical actin at pHo 7.9 and 7.4 vs. 6.9 after 90 min of chemical anoxia. After 15 min of ATP depletion, G-actin, quantified by the deoxyribonuclease assay, decreased from 53.7 +/- 0.8 to 43.2 +/- 1.5 microgram/mg protein at pHo 6.9 vs. 37.6 +/- 1.8 microgram/mg protein at pHo 7.4 (P < 0.001). After 60 min, there still was significantly less conversion of G-actin to F-actin at pHo 6.9 vs. 7.4, with a decrease from 55.9 +/- 2.0 to 39.6 +/- 2.0 micrograms/mg protein at 6.9 vs. 35.8 +/- 2.4 at 7.4 micrograms/mg protein (P < 0.05). Furthermore, extracellular acidosis during the phase of ATP repletion resulted in more rapid normalization of cellular G-actin levels (95 +/- 3% of control vs. 82 +/- 2% for pH 6.9 vs. 7.4, respectively, P < 0.01). Together, these findings indicate the actin cytoskeleton is better preserved in an acidic environment during ATP depletion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Extracellular acidosis minimizes actin cytoskeletal alterations during ATP depletion. 794 55

The activity of deoxyribonucleases was altered in the myocardium of New Zealand rabbits under normal conditions, in diabetes mellitus as well as in various experiments, where model heart perfusion was carried out using media of various ion composition and pH value. Studies of Ca2+, MG(2+)- dependent deoxyribonuclease from myocardial nuclear extracts exhibited that protective cell mechanisms appear t be induced at the first steps of tissue ischemic impairments as well as that diabetes decreased cardiac sensitivity to ischemia.
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PMID:[Nuclear endo-DNAse from rabbit myocardium in ischemia and diabetes mellitus]. 858 87

The small heat-shock proteins appear to have a regulatory role in actin dynamics. Since cytoskeletal disruption is integral to ischemic renal injury, we evaluated expression and intracellular distribution of heat-shock protein 25 (HSP-25) in rat renal cortex after 45 min of renal ischemia. HSP-25 was constitutively expressed and induced by ischemia with peak levels reached by 6 h reflow. Ischemia caused a shift of HSP-25 from the detergent-soluble into the insoluble cytoskeletal fraction. By 2 h reflow, the majority of HSP-25 had redistributed into the soluble fraction. HSP-25 was predominantly localized in a subapical distribution in control proximal tubules, a pattern intermediate between deoxyribonuclease (DNase)-reactive and filamentous actin. After ischemia, HSP-25 dispersed through the cytoplasm with small punctate accumulations similar to DNase-reactive actin. During later reflow, all three proteins were found in coarse intracytoplasmic accumulations; however, HSP-25 and DNase-reactive actin were in separate accumulations. HSP-25 and microfilamentous actin staining returned to the subapical domain. Thus the temporal and spatial patterns of HSP-25 induction and distribution suggest specific interactions between HSP-25 and actin during the early postischemic reorganization of the cytoskeleton. HSP-25 may have additional roles distinct from actin dynamics later in the course of postischemic recovery.
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PMID:Heat-shock protein 25 induction and redistribution during actin reorganization after renal ischemia. 945 42

The Ref-1 protein is a bifunctional nuclear enzyme involved in repair of DNA lesions and in redox regulation of DNA-binding activity of AP-1 family members, such as Fos and Jun transcription factors. In the present study, we demonstrate by in situ hybridization that transient global ischemia induced by cardiac arrest activates ref-1 mRNA expression in the granular cells of the rat dentate gyrus after 6 h and in CA1 pyramidal neurons of the hippocampus proper after 24 h, respectively. Immunohistochemical analysis revealed nuclear accumulation of Ref-1 protein in granular cells of the ischemia-resistant dentate gyrus, whereas Ref-1 protein expression progressively decreased in vulnerable CA1 neurons of the post-ischemic hippocampus from 24 h onwards. At the same time point, intense nuclear c-Jun immunoreactivity was observed in both neuronal cell populations. Our data suggest that oxidative stress induced by ischemia-reperfusion may increase neuronal ref-1 expression. However, inability of ref-1 mRNA translation and nuclear translocation of encoded protein in CA1 pyramidal neurons may inhibit repair of oxidative DNA damage or cellular adaptive responses leading to delayed neuronal cell death.
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PMID:Expression of nuclear redox factor ref-1 in the rat hippocampus following global ischemia induced by cardiac arrest. 949 40

Proliferating cell nuclear antigen (PCNA) is required for completion of the DNA synthesis step of DNA replication as well as nucleotide excision repair (NER) of damaged DNA. We investigated the expression of PCNA mRNA and the levels of PCNA protein in the adult rat hippocampus following normo- and hypothermic global forebrain ischemia. Hypothermia protected the CA1 neurons from ischemic damage. A constitutive expression of PCNA mRNA and protein was detected in all hippocampal subfields, as well as in other brain regions. During reperfusion, PCNA mRNA levels were up-regulated in the vulnerable CA1 subfield at 36 h following normothermic ischemia. In hypothermia, this induction appeared already after 18 h. Following normothermic ischemia, nuclear PCNA immunoreactivity was largely abolished during reperfusion in the vulnerable CA1 neurons, prior to cell death. In contrast, total PCNA protein content of this region, as measured by Western blotting, remained largely unchanged. In the CA3 region, a transient decrease in nuclear PCNA immunoreactivity was observed. In the dentate gyrus region, no down-regulation of nuclear or total PCNA protein was observed during reperfusion. Following hypothermic ischemia, the PCNA protein levels did not decrease in any of the hippocampal subregions. In contrast, no change in the levels of Ref-1, a protein involved in base excision DNA repair (BER), was observed following normo- or hypothermic ischemia. Our findings indicate an altered functional state of PCNA protein in the ischemia-sensitive CA1 neurons suggesting that DNA repair processes are affected in these post-mitotic cells following ischemia. Impaired DNA repair may play a role in the development of postischemic neuronal damage.
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PMID:Changes in proliferating cell nuclear antigen, a protein involved in DNA repair, in vulnerable hippocampal neurons following global cerebral ischemia. 975 27

Cerebral ischemia and the aftermath of reperfusion form a hypoxic/hyperoxic sequence of events that can trigger oxidative stress response cascades in neurons of the central nervous system. After transient ischemia there is an increase in intracellular Ca2+ release, extracellular glutamate, reactive oxygen species (ROS) and nitric oxide, genotoxic events that stimulate DNA repair. Increased oxidative stress and interrupted blood flow in ischemia, like DNA repair, also deplete cellular ATP and commit neurons to apoptosis. We report that levels of the DNA repair enzyme apurinic/apyrimidinic endonuclease (APE/Ref-1) decreased significantly in the hippocampus but not other brain areas after 6 h of reperfusion following an induced ischemic insult. This specific inhibition of APE/Ref-1 expression may affect the extent of apoptosis after ischemia.
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PMID:APE/Ref-1 responses to ischemia in rat brain. 992 39

The authors examined the protein expression of apurinic/apyrimidinic endonuclease (APE/Ref-1), a multifunctional protein in the DNA base excision repair pathway, before and after transient focal ischemia in mice. Immunohistochemistry showed the nuclear expression of APE/Ref-1 in the entire region of the control brains. Nuclear immunoreactivity was decreased as early as 5 minutes after 60 minutes of ischemia in the ischemic core, which was followed by a significant reduction of APE/Ref-1-positive cells in the entire middle cerebral artery territory. Western blot analysis of the sample from the nonischemic brain showed a characteristic 37-kDa band, which was reduced after ischemia. A significant amount of DNA fragmentation was observed at 24 hours, but not at 4 hours, after ischemia. The authors' data provide the first evidence that APE/Ref-1 rapidly decreases after transient focal ischemia, and that this reduction precedes the peak of DNA fragmentation in the brain regions that are destined to show necrosis and apoptosis. Although further examination is necessary to elucidate the direct relationship between the APE/Ref-1 decrease and ischemic necrosis and apoptosis, our results suggest the possibility that rapid decrease of APE/Ref-1 and the failure of the DNA repair mechanism may contribute to necrosis or apoptosis after transient focal ischemia.
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PMID:Early decrease of apurinic/apyrimidinic endonuclease expression after transient focal cerebral ischemia in mice. 1032 16

We examined the effects of the free radical scavenger, 21-aminosteroid, on apurinic/apyrimidinic endonuclease (APE/Ref-1) protein expression and subsequent infarction volume after photothrombotic cortical cerebral ischemia in mice. Immunohistochemistry and Western blot analysis showed a significant reduction in APE/Ref-1 expression 6 and 24 h after ischemia in untreated animals, whereas in drug-treated animals the reduction was much less at the same time points. The administration of 21-aminosteroid significantly decreased subsequent infarction volume 3 days after ischemia. These data suggest that 21-aminosteroid prevents the early decrease of APE/Ref-1 expression, thereby reducing cortical infarction after photothrombotic cerebral ischemia.
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PMID:Neuroprotective effects of an antioxidant in cortical cerebral ischemia: prevention of early reduction of the apurinic/apyrimidinic endonuclease DNA repair enzyme. 1064 98

The temporospatial expression pattern of the nuclear DNA repair enzyme redox factor-1 (ref-1), the p53-activated gene (pag) 608 and the effector caspase-3 was examined by in situ hybridization histochemistry in gerbils subjected to two 10-min episodes of unilateral common carotid artery occlusion, separated by 5h. Gene responses were correlated with the metabolic state, as revealed by regional adenosine 5'-triphosphate bioluminescent imaging, and with the degree of histological damage, as assessed by haematoxylin-eosin staining and terminal deoxynucleotidyl transferase-mediated-dUTP nick end labeling (TUNEL), in order to evaluate the role of these genes in the maturation of injury. Focal infarcts developed in the dorsolateral cerebral cortex at the bregma level and the nucleus caudate-putamen within four days after repeated unilateral ischemia, as indicated by a secondary adenosine 5'-triphosphate loss after initial adenosine 5'-triphosphate recovery and by histomorphological signs of pannecrosis. The more caudal cortex at hippocampal levels and the hippocampus (CA1>CA3 area), however, exhibited selective neuronal injury without adenosine 5'-triphosphate depletion. TUNEL+ cells appeared starting 5h after repeated unilateral ischemia. TUNEL+ cells reached maximum levels in the caudate-putamen at 12-24h, but much later in the cortex and hippocampus at two days after ischemia. Remarkably few TUNEL+ cells were noticed in the thalamus, where adenosine 5'-triphosphate state did not recover after reperfusion. Following repeated unilateral ischemia, a transient elevation of ref-1 mRNA was detected after 5h in the cerebral cortex and hippocampal CA1 area. Ref-1 mRNA levels decreased within 12-24h, before the onset of tissue damage. Subsequently, pag608 and caspase-3 mRNA levels increased, closely in parallel with the appearance of DNA fragmented cells, but slightly prior to the deterioration of adenosine 5'-triphosphate state. In the caudate-putamen, pag608 and caspase-3 mRNAs reached maximum levels already 12-24h after repeated common carotid artery occlusion, when DNA fragmentation was most prominent, and declined thereafter. In the cortex and hippocampal CA1-3 areas, where DNA damage appeared more slowly, pag608 and caspase-3 mRNAs were induced starting 24h after ischemia, and remained elevated even after two to four days. The levels of pag608 and caspase-3 mRNAs were similar at rostral and caudal levels of the cortex, as well as in the hippocampal CA1 and CA3 area, although the degree of injury differed considerably between these structures. Notably, pag608 and caspase-3 mRNAs were not elevated in the thalamus after repeated unilateral ischemia. The present report shows a close temporal association between the induction of ref-1, pag608 and caspase-3 mRNAs, the manifestation of cell injury and the secondary adenosine 5'-triphosphate depletion in infarcting brain areas, suggesting (i) that de novo responses of these genes may be involved in the maturation of cell injury and (ii) that apoptotic programs and the secondary deterioration of cerebral energy state may interfere with each other after ischemia.
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PMID:Expression of redox factor-1, p53-activated gene 608 and caspase-3 messenger RNAs following repeated unilateral common carotid artery occlusion in gerbils--relationship to delayed cell injury and secondary failure of energy state. 1118 42

Deoxyribonucleic acid fragmentation at nucleosomal junctions is a hallmark of neuronal apoptosis in ischemic brain injury, for which the mechanism is not fully understood. Using the in vitro cell-free apoptosis assay, the authors found that caspase-3-dependent deoxyribonuclease activity caused internucleosomal DNA fragmentation in brain-cell extracts in a rat model of transient focal ischemia. This in vitro deoxyribonuclease activity was completely inhibited by purified inhibitor of caspase-activated deoxyribonuclease protein, the specific endogenous inhibitor of caspase-activated deoxyribonuclease, or by caspase-activated deoxyribonuclease immunodepletion. The induction of the deoxyribonuclease activity was correlated with caspase-3 activation and caspase-3-mediated degradation of inhibitor of caspase-activated deoxyribonuclease. Furthermore, inhibiting caspase-3-like protease activity prevented the endogenous induction of internucleosomal DNA fragmentation in the ischemic brain. These results suggest that caspase-3-dependent caspase-activated deoxyribonuclease activity plays an important role in mediating DNA fragmentation after focal ischemia.
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PMID:Induction of caspase-activated deoxyribonuclease activity after focal cerebral ischemia and reperfusion. 1180 89


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