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

Heat shock protein (Hsp)70 can suppress both necrosis and apoptosis induced by various injuries in vivo and in vitro. However, the relative importance of different functions and binding partners of Hsp70 in ischemic protection is unknown. To explore this question, we tested the ability of Hsp70-K71E, an adenosine triphosphate (ATP)ase-deficient point mutant, and Hsp70-381-640, a deletion mutant lacking the ATPase domain and encoding the carboxyl-terminal portion, to protect against ischemia-like injury in vivo and in vitro. Heat shock protein 70-wild type (-WT), -K71E, -381-640, and control vector plasmid LXSN were expressed in primary murine astrocyte cultures. Astrocytes overexpressing Hsp70-WT, -K71E, or -381-640 were all significantly protected from 4 h combined oxygen-glucose deprivation and 24 h reperfusion when assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay or propidium iodide staining and cell counting (P < 0.05). Brains of rats were transfected with plasmids encoding Hsp70-WT, -K71E, -381-640, or LXSN 24 h before 2 h middle cerebral artery occlusion followed by 24 h reperfusion. Animals that overexpressed either of the mutant proteins or Hsp70-WT had significantly better neurological scores and smaller infarcts than control animals. Protection by both mutants was associated with reduced protein aggregation, as assessed by ubiquitin immunohistochemistry and reduced nuclear translocation of apoptosis-inducing factor. The results show that the carboxyl-terminal portion of Hsp70 is sufficient for neuroprotection. This indicates that neither the ability to fold denatured proteins nor interactions with cochaperones or other proteins that bind the amino-terminal half of Hsp70 are essential to ischemic protection.
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PMID:The carboxyl-terminal domain of inducible Hsp70 protects from ischemic injury in vivo and in vitro. 1629 51

Extracellular acidic pH was found to induce an outwardly rectifying Cl- current (I(Cl,acid)) in mouse ventricular cells, with a half-maximal activation at pH 5.9. The current showed the permeability sequence for anions to be SCN- > Br- > I- > Cl- > F- > aspartate, while it exhibited a time-dependent activation at large positive potentials. Similar currents were also observed in mouse atrial cells and in atrial and ventricular cells from guinea pig. Some Cl- channel blockers (DIDS, niflumic acid, and glibenclamide) inhibited ICl,acid, whereas tamoxifen had little effect on it. Unlike volume-regulated Cl- current (ICl,vol) and CFTR Cl- current (ICl,CFTR), ICl,acid was independent of the presence of intracellular ATP. Activation of ICl,acid appeared to be also independent of intracellular Ca2+ and G protein. ICl,acid and ICl,vol could develop in an additive fashion in acidic hypotonic solutions. Isoprenaline-induced ICl,CFTR was inhibited by acidification in a pH-dependent manner in guinea pig ventricular cells. Our results support the view that ICl,acid and ICl,vol stem from two distinct populations of anion channels and that the ICl,acid channels are present in cardiac cells. ICl,acid may play a role in the control of action potential duration or cell volume under pathological conditions, such as ischemia-related cardiac acidosis.
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PMID:Acidic extracellular pH-activated outwardly rectifying chloride current in mammalian cardiac myocytes. 1633 31

The cardioprotective actions of nitric oxide (NO) have largely been attributed to cGMP. NO may, however, elicit some biological actions independently of cGMP. We tested the hypothesis that the NO donor sodium nitroprusside specifically protects isolated cardiomyocytes from injury at least in part independently of its ability to elevate cGMP by using metabolic inhibition to simulate ischemia. Metabolic inhibition-induced injury of adult rat cardiomyocytes (increased activity of lactate dehydrogenase and creatine kinase) was significantly reduced by sodium nitroprusside by at least 30% at all concentrations studied (0.3-100 microM). Sodium nitroprusside (1 microM) increased cardiomyocyte cGMP content, but neither a stable analogue of cGMP (8-bromo-cGMP) nor a potent cGMP stimulus (atrial natriuretic peptide) mimicked the protective effects of sodium nitroprusside. Moreover, inhibition of soluble guanylyl cyclase failed to inhibit sodium nitroprusside cardiomyocyte protection. Conversely, inhibition of either ATP-sensitive potassium (K(ATP)) channels with glibenclamide (10 microM) or calcium-sensitive potassium (K(Ca)) channels with tetraethylammonium bromide (1 mM) or iberiotoxin (20 nM) markedly attenuated the cardioprotective actions of sodium nitroprusside. In conclusion, sodium nitroprusside protects isolated cardiomyocytes from metabolic inhibition independently of cGMP; rather, inhibition of K(Ca) and K(ATP) channels reverses the sodium nitroprusside actions, thus unmasking another mechanism for NO-mediated protection in cardiomyocytes.
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PMID:Sodium nitroprusside protects adult rat cardiac myocytes from cellular injury induced by simulated ischemia: role for a non-cGMP-dependent mechanism of nitric oxide protection. 1642 79

Ischemia-reperfusion (I/R) injury causes skeletal muscle infarction and ischemic preconditioning (IPC) augments ischemic tolerance in animal models. To date, this has not been demonstrated in human skeletal muscle. This study aimed to develop an in vitro model to investigate the efficacy of simulated IPC in human skeletal muscle. Human skeletal muscle strips were equilibrated in oxygenated Krebs-Henseleit-HEPES buffer (37 degrees C). Aerobic and reperfusion phases were simulated by normoxic incubation and reoxygenation, respectively. Ischemia was simulated by hypoxic incubation. Energy store, cell viability, and cellular injury were assessed using ATP, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and lactate dehydrogenase (LDH) assays, respectively. Morphological integrity was assessed using electron microscopy. Studies were designed to test stability of the preparation (n = 5-11) under normoxic incubation over 24 h; the effect of 1, 2, 3, 4, or 6 h hypoxia followed by 2 h of reoxygenation; and the protective effect of hypoxic preconditioning (HPC; 5 min of hypoxia/5 min of reoxygenation) before 3 h of hypoxia/2 h of reoxygenation. Over 24 h of normoxic incubation, muscle strips remained physiologically intact as assessed by MTT, ATP, and LDH assays. After 3 h of hypoxia/2 h of reoxygenation, MTT reduction levels declined to 50.1 +/- 5.5% (P < 0.05). MTT reduction levels in HPC (82.3 +/- 10.8%) and normoxic control (81.3 +/- 10.2%) groups were similar and higher (P < 0.05) than the 3 h of hypoxia/2 h of reoxygenation group (45.2 +/- 5.8%). Ultrastructural morphology was preserved in normoxic and HPC groups but not in the hypoxia/reoxygenation group. This is the first study to characterize a stable in vitro model of human skeletal muscle and to demonstrate a protective effect of HPC in human skeletal muscle against hypoxia/reoxygenation-induced injury.
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PMID:Development of an in vitro model for study of the efficacy of ischemic preconditioning in human skeletal muscle against ischemia-reperfusion injury. 1704 28

Recent reports and our previous study suggest that mast cells play a crucial role in the pathological processes that follow cerebral ischemia. In this study, the effect of mast cells on neuron injury after cerebral ischemia was determined by adding in vitro ischemia-induced supernatant from mast cells to neurons and PC12 cells under the same conditions (oxygen-glucose deprivation, OGD). The degree of cell injury was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-dipheny-ltetrazolium bromide (MTT) assay. Mast cell-derived supernatant protected against OGD-induced injury of PC12 cells and neurons, and this protection was reversed by a histamine H1 antagonist and by anti-histamine serum, but not by an H2 antagonist. However, histamine and nerve growth factor (NGF) added separately or together did not have protective effects against OGD-induced injury. These results indicate that mast cell-derived protection during in vitro ischemia is histamine-dependent, and involves cooperation with other mediators, but not NGF.
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PMID:Mast cell-derived mediators protect against oxygen-glucose deprivation-induced injury in PC12 cells and neurons. 1766 24

In view of the ability of neurotensin (NT) to increase glutamate release, the role of NT receptor mechanisms in oxygen-glucose deprivation (OGD)-induced neuronal degeneration in cortical cultures has been evaluated by measuring lactate dehydrogenase (LDH) levels, mitochondrial dehydrogenase activity with 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide levels, and microtubule-associated protein 2 (MAP2) immunoreactivity. Apoptotic nerve cell death was analyzed measuring chromatin condensation with Hoechst 33258, annexin V staining, and caspase-3 activity. Furthermore, the involvement of glutamate excitotoxicity in the neurodegeneration-enhancing actions of NT was analyzed by measurement of extracellular glutamate levels. NT enhanced the OGD-induced increase of LDH, endogenous extracellular glutamate levels, and apoptotic nerve cell death. In addition, the peptide enhanced the OGD-induced loss of mitochondrial functionality and increase of MAP2 aggregations. These effects were blocked by the neurotensin receptor 1 (NTR1) antagonist SR48692. Unexpectedly, the antagonist at 100 nM counteracted not only the NT effects but also some OGD-induced biochemical and morphological alterations. These results suggest that NTR1 receptors may participate in neurodegenerative events induced by OGD in cortical cultures, used as an in vitro model of cortical ischemia. The NTR1 receptor antagonists could provide a new tool to explore the clinical possibilities and thus to move from chemical compound to effective drug.
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PMID:Neurotensin receptor involvement in the rise of extracellular glutamate levels and apoptotic nerve cell death in primary cortical cultures after oxygen and glucose deprivation. 1806 61

Oxygen-regulated protein 150 (ORP150) is an inducible endoplasmic reticulum (ER) chaperone molecule that is upregulated after numerous cellular insults and has a cytoprotective role in renal, neural, and cardiac models of ischemia-reperfusion injury. ORP150 also has been shown to play a role in cellular Ca(2+) homeostasis, and in turn, regulating calpain activity. In this study, we identified ORP150 in whole rat renal cortical mitochondria and matrix fractions, demonstrated the targeting of an ORP150-GFP construct to the mitochondria of NIH-3T3 cells, and showed that the NH(2)-terminal 13 amino acids of ORP150 are sufficient for this translocation. ORP150 expression was found to be regulated by the anti-C/enhancer-binding protein homologous protein (CHOP)/GADD153 transcription factor and ORP150 levels increased in the mitochondria and ER of COS-7 cells after diverse stresses, including hypoxia, serum starvation, prolyl hydroxylase inhibition with dimethyloxaloylglycine, and exposure to tunicamycin, ethidium, bromide, and 2-deoxyglucose. Induction of the mitochondrial specific stress response in COS-7 cells through expression of an ornithine transcarbamylase mutant (Delta OTC) increased mitochondrial ORP150 levels and mitochondrial calpain activity. To determine whether mitochondrial ORP150 and mitochondrial calpain 10 interact, rat cortical mitochondria exposed to Ca(2+) resulted in ORP150 cleavage in a calpain inhibitor-dependent manner, revealing that ORP150 is a substrate and may be regulated by calpain 10. These data reveal a novel cellular localization for ORP150 and that mitochondrial ORP150 is upregulated by CHOP/GADD153 in response to mitochondrial and ER stress. Our data also reveal that ORP150 is a substrate for mitochondrial calpain 10.
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PMID:Targeting of the molecular chaperone oxygen-regulated protein 150 (ORP150) to mitochondria and its induction by cellular stress. 1809 45

We studied hippocampal cellular proliferation and neurogenesis processes in a model of transient global cerebral ischemia in gerbils by labelling dividing cells with 5'-Bromo-2'-deoxyuridine (BrdU). Surrounding the region of selective neuronal death (CA1 pyramidal layer of the hippocampus), an important increase in reactive astrocytes and BrdU-labelled cells was detected 5 days after ischemia. A similar result was found in the dentate gyrus (DG) 12 days after ischemia. The differentiation of the BrdU+ cells was investigated 28 days after BrdU administration by analyzing the morphology, anatomic localization and cell phenotype by triple fluorescent labelling (BrdU, adult neural marker NeuN and DNA marker TOPRO-3) using confocal laser-scanning microscopy. This analysis showed increased neurogenesis in the DG in case of ischemia and triple positive labelling in some newborn cells in CA1. Seven brain hemispheres from gerbils subjected to ischemia did not develop CA1 neuronal death; hippocampus from these hemispheres did not show any of the above mentioned findings. Our results indicate that ischemia triggers proliferation in CA1 and neurogenesis in the DG in response to CA1 pyramidal neuronal death, independently of the reduced cerebral blood flow or the cell migration from subventricular zone (SVZ).
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PMID:Ischemia induces cell proliferation and neurogenesis in the gerbil hippocampus in response to neuronal death. 1832 20

Catalpol, an iridoid glycoside abundant in the roots of Rehmannia glutinosa, has been previously found to prevent the loss of CA1 hippocampal neurons and to reduce working errors in gerbils after ischemia-reperfusion injury. In the present study, we investigated the effects of catalpol on astrocytes in an ischemic model to further characterize its neuroprotective mechanisms. Primary cultured astrocytes exposed to oxygen-glucose deprivation (OGD) followed by reperfusion (adding back oxygen and glucose, OGD-R), were used as an in vitro ischemic model. Treatment of the astrocytes with catalpol during ischemia-reperfusion increased astrocyte survival significantly in a concentration-dependent manner, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release and morphological observation. In addition, catalpol prevented the decrease in mitochondrial membrane potential, inhibited the formation of reactive oxygen species (ROS) and the production of nitric oxide (NO), decreased the level of lipid peroxide and the activity of inducible nitric oxide synthase (iNOS), and elevated the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and the content of glutathione (GSH). Our results suggest that catalpol exerts the most significant cytoprotective effect on astrocytes by suppressing the production of free radicals and elevating antioxidant capacity.
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PMID:Catalpol protects primary cultured astrocytes from in vitro ischemia-induced damage. 1833 48

Carthamus tinctorius L. (safflower) is one of the most commonly used Chinese herbal medicines to prevent and treat cardiac disease in clinical practice. However, the mechanisms responsible for such protective effects remain largely unknown. In this study, we investigated the anti-myocardial ischemia effects of a purified extract of C. tinctorius (ECT) both in vivo and in vitro. An animal model of myocardial ischemia injury was induced by left anterior descending coronary artery occlusion in adult rats. Pretreatment with ECT (100, 200, 400, 600 mg/kg body wt.) could protect the heart from ischemia injury by limiting infarct size and improving cardiac function. In the in vitro experiment, neonatal rat ventricular myocytes were incubated to test the direct cytoprotective effect of ECT against H(2)O(2) exposure. Pretreatment with 100-400 microg/ml ECT prior to H(2)O(2) exposure significantly increased cell viability as revealed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. ECT also markedly attenuated H(2)O(2)-induced cardiomyocyte apoptosis, as detected by Annexin V and PI double labeling with flow cytometry. The intracellular level of reactive oxygen species (ROS) was shown by 2',7'-dichlorofluorescin diacetate (DCFH-DA), and ECT pretreatment significantly inhibited H(2)O(2)-induced ROS increase. We made a preliminary examination of the signaling cascade involved in ECT mediated anti-apoptotic effects. Phosphatidylinositol 3 kinase (PI3K) inhibitor (LY294002) blocked the cytoprotective effect conferred by ECT. Taken together, our findings provide the first evidence that the cardioprotective effects of ECT in myocardial ischemia operate partially through reducing oxidative stress induced damage and apoptosis. The protection is achieved by scavenging of ROS and mediating the PI3K signaling pathway.
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PMID:Protective effects of purified safflower extract on myocardial ischemia in vivo and in vitro. 1939 8


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