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)

The effects of the exposure of hippocampal slices to brief periods of ischemic-like conditions on the tyrosine phosphorylation of proteins and glycoproteins were investigated. Freshly prepared hippocampal slices contained a range of tyrosine-phosphorylated proteins and two prominent tyrosine-phosphorylated glycoproteins of apparent M(r) 110,000 (GP110) and 180,000, which we have previously shown to correspond to the postsynaptic density (PSD)-associated glycoprotein PSD-GP180. When hippocampal slices were incubated in oxygenated Krebs-Ringer buffer containing 10 mM glucose (KRB), there was a transient increase in the tyrosine phosphorylation of a protein of M(r) 42,000 (p42) and a pronounced increase in the tyrosine phosphorylation of GP110. After these initial changes, the tyrosine phosphorylation of all proteins remained constant for at least 60 min. In vitro "ischemia" was achieved by transferring slices that had been preincubated for 60 min in KRB to KRB that had been equilibrated with N2 instead of O2 and that did not contain glucose. Tyrosine-phosphorylated GP110 and PSD-GP180 could no longer be detected after 10 min of exposure of the slices to ischemic-like conditions. GP110 was rapidly rephosphorylated on tyrosine after transfer of slices back to oxygenated, glucose-containing buffer. In contrast, short periods of ischemia (5 or 10 min) resulted in the long-term loss of phosphotyrosine [Tyr(P)]-PSD-GP180 so that it was not detected even after 60 min of reincubation in oxygenated KRB. The sustained decrease in tyrosine phosphorylation of PSD-GP180 after ischemia was Ca2+ dependent, the levels of Tyr(P)-PSD-GP180 slowly increasing to preischemic values if Ca2+ was omitted from the incubation media.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tyrosine phosphorylation in a model of ischemia using the rat hippocampal slice: specific, long-term decrease in the tyrosine phosphorylation of the postsynaptic glycoprotein PSD-GP180. 756 82

p38MAPK has been implicated in the regulation of proinflammatory cytokines and apoptosis in vitro. To understand its role in neurodegeneration, we determined the time course and localization of the dually phosphorylated active form of p38MAPK in hippocampus after global forebrain ischemia. Phosphorylated p38MAPK and mitogen-activated protein kinase-activated protein 2 activity increased over 4 days after ischemia. Phosphorylated p38MAPK immunoreactivity was observed in microglia in regions adjacent to, but not in, the dying CA1 neurons. In contrast, neither c-Jun N-terminal kinase 1 nor p42/p44MAPK activity was altered after ischemia. These results provide the first evidence for localization of activated p38MAPK in the CNS and support a role for p38MAPK in the microglial response to stress.
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PMID:Activation of p38MAPK in microglia after ischemia. 952 96

Using conscious rabbits, we examined the effect of ischemic preconditioning (PC) on p44 and p42 mitogen-activated protein kinases (MAPKs). We found that both isoforms contribute significantly to total MAPK activity in the heart (in-gel kinase assay: p44, 59 +/- 1%; p42, 41 +/- 1%). Ischemic PC (6 cycles of 4-min occlusion/4-min reperfusion) elicited a pronounced increase in total cellular MAPK activity (+89%). This increase, which occurred exclusively in the nuclear fraction, was contributed by both isoforms (in-gel kinase assay: p44, +97%; p42, +210%) and was accompanied by migration of the two proteins from the cytosolic to the nuclear compartment. In control rabbits, MAPK kinase (MEK)1 and MEK2, direct activators of p44 and p42 MAPKs, were located almost exclusively in the cytosolic fraction. Ischemic PC induced a marked increase in cytosolic MEK activity (+164%), whereas nuclear MEK activity did not change, indicating that MEK-induced activation of MAPKs occurred in the cytosolic compartment. Activation of MAPKs after ischemic PC was completely blocked by the protein kinase C (PKC) inhibitor chelerythrine. Selective overexpression of PKC-epsilon in adult rabbit cardiomyocytes induced activation of both p44 and p42 MAPKs and reduced lactate dehydrogenase release during simulated ischemia-reperfusion, which was abolished by the MEK inhibitor PD-98059. The results demonstrate that 1) ischemic PC induces a rapid activation of p44 and p42 MAPKs in hearts of conscious rabbits; 2) the mechanism of this phenomenon involves activation of p44 and p42 MAPKs in the cytosol and their subsequent translocation to the nucleus; and 3) it occurs via a PKC-mediated signaling pathway. The in vitro data implicate PKC-epsilon as the specific isoform responsible for PKC-induced MAPK activation and suggest that p44/p42 MAPKs contribute to PKC-epsilon-mediated protection against simulated ischemia. The results are compatible with the hypothesis that p44 and p42 MAPKs may play a role in myocardial adaptations to ischemic stress.
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PMID:PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits. 1033 Feb 29

Extracellular purines, including adenosine and ATP, are potent endogenous immunomodulatory molecules. Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or ischemia. In the present study, we investigated whether extracellular inosine can affect inflammatory/immune processes. In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1alpha, and IFN-gamma, but failed to alter the production of the anti-inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by nucleoside transporters and was partially reversed by blockade of adenosine A1 and A2 receptors. Inosine inhibited cytokine production by a posttranscriptional mechanism. The activity of inosine was independent of activation of the p38 and p42/p44 mitogen-activated protein kinases, the phosphorylation of the c-Jun terminal kinase, the degradation of inhibitory factor kappaB, and elevation of intracellular cAMP. Inosine suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model. Taken together, inosine has multiple anti-inflammatory effects. These findings, coupled with the fact that inosine has very low toxicity, suggest that this agent may be useful in the treatment of inflammatory/ischemic diseases.
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PMID:Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. 1062 51

Urocortin (UCN) is a peptide related to hypothalamic corticotrophin-releasing hormone and binds with high affinity to corticotrophin-releasing hormone receptor-2beta, which is expressed in the heart. In this study, we report that UCN prevented cell death when administered to primary cardiac myocyte cultures both prior to simulated hypoxia/ischemia and at the point of reoxygenation after simulated hypoxia/ischemia. UCN-mediated cell survival was measured by trypan blue exclusion, 3'-OH end labeling of DNA (TUNEL), annexin V, and fluorescence-activated cell sorting. To explore the mechanisms that could be responsible for this effect, we investigated the involvement of MAPK-dependent pathways. UCN caused rapid phosphorylation of ERK1/2-p42/44, and PD98059, which blocks the MEK1-ERK1/2-p42/44 cascade, also inhibited the survival-promoting effect of UCN. Most important, UCN reduced damage in isolated rat hearts ex vivo subjected to regional ischemia/reperfusion, with the protective effect being observed when UCN was given either prior to ischemia or at the time of reperfusion after ischemia. This suggests a novel function of UCN as a cardioprotective agent that could act when given after ischemia, at reperfusion.
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PMID:Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway. 1072 88

Activation of protein kinase C (PKC) and more recently mitogen-activated protein kinases (MAPKs) have been associated with the cardioprotective effect of ischemic preconditioning. We examined the interplay between these kinases in a characterized model of ischemic preconditioning in cultured rat neonatal ventricular cardiocytes where ectopic expression of active PKC-delta results in protection. Two members of the MAPK family, p38 and p42/44, were activated transiently during preconditioning by brief simulated ischemia/reoxygenation. Overexpression of active PKC-delta, rather than augmenting, completely abolished this activation. We therefore determined whether a similar process occurred during lethal prolonged simulated ischemia. In contrast to ischemia, brief, lethal-simulated ischemia activated only p38 (2.8+/-0.45 vs. basal, P<0.01), which was attenuated by expression of active PKC-delta or by preconditioning (0.48+/-0.1 vs. ischemia, P<0.01). To determine whether reduced p38 activation was the cause or an effect of protection, we used SB203580, a p38 inhibitor. SB203580 reduced ischemic injury (CK release 38.0+/-3.1%, LDH release 77.3+/-4.0%, and MTT bioreduction 127.1+/-4.8% of control, n=20, P<0.05). To determine whether p38 activation was isoform selective, myocytes were infected with adenoviruses encoding wild-type p38alpha or p38beta. Transfected p38alpha and beta show differential activation (P<0.001) during sustained simulated ischemia, with p38alpha remaining activated (1.48+/-0.36 vs. basal) but p38beta deactivated (0.36+/-0.1 vs. basal, P<0.01). Prior preconditioning prevented the activation of p38alpha (0.65+/-0.11 vs. ischemia, P<0.05). Moreover, cells expressing a dominant negative p38alpha, which prevented ischemic p38 activation, were resistant to lethal simulated ischemia (CK release 82.9+/-3.9% and MTT bioreduction 130.2+/-6.5% of control, n=8, P<0.05). Thus, inhibition of p38alpha activation during ischemia reduces injury and may contribute to preconditioning-induced cardioprotection in this model.
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PMID:The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. 1105 45

Stimulation of the delta(1)-opioid receptor has been shown to trigger ischemic preconditioning (IPC). Additionally, myocardial ischemia/reperfusion induces the activation of extracellular signal-regulated kinase (ERK). Therefore, we examined the role of ERK in acute cardioprotection induced by delta(1)-opioid receptor stimulation or IPC. Infarct size (IS) was expressed as a percentage of the area at risk (AAR). Control animals had an IS/AAR of 60.6 +/- 1.8. IPC and delta(1)-opioid receptor stimulation with TAN-67 reduced IS/AAR (8.2 +/- 1.3 and 30.2 +/- 2.4). Inhibition of ERK with the selective MEK-1 antagonist, PD 098059 during IPC or TAN-67 administration significantly reduced cardioprotection (41.5 +/- 6.4 and 63.0 +/- 4.8). Western Blot analysis and subsequent densitometry corroborated these observations. Control, TAN-67-, or IPC-treated hearts were harvested after 0, 5, 15, and 30 min of ischemia or 5, 30, and 60 min of reperfusion and separated into cytosolic and nuclear fractions. Both isoforms of ERK (p44 and p42) rapidly increased to greater levels throughout reperfusion in the nuclear fraction of IPC- and opioid-treated versus control rats, however, this increase was not attenuated by PD 098059. Conversely, the rapid activation of the 44-kDa isoform of ERK after 5 min of reperfusion in the cytosolic fraction was significantly increased in IPC- and opioid-treated hearts versus control, and this increase was abolished by pretreatment with PD 098059. Additionally, p42 was activated in the cytosolic fraction of IPC-treated animals. These results suggest a key role for the 44-kDa isoform of ERK in the cytoplasm during cardioprotection induced by either IPC or stimulation of the delta(1)-opioid receptor.
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PMID:Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection. 1116 Jun 53

Previously we reported that ischemia results in apoptosis and is accompanied by phosphorylation on Tyr-701 and increased expression and transcriptional activity of the signal transducer and activator of transcription-1 (STAT-1). In the present study, we show that exposure of cardiomyocytes to ischemia induced the phosphorylation of STAT-1 at another site, Ser-727. Moreover, STAT-1 is critical for the induction of Fas receptor and Fas ligand expression by ischemia/reperfusion (I/R). Transcriptional activation of Fas and FasL was dependent on Ser-727 of STAT-1 but was independent of Tyr-701. Similarly, Ser-727 but not Tyr-701 was required for enhancement of cardiomyocyte cell death by STAT-1 during I/R. In addition, inhibition of the p38 pathway prevented the induction and transcriptional activation of Fas and FasL in cardiac cells exposed to I/R, whereas inhibition of p42/p44 MAPK had no effect. Finally, I/R also induced phosphorylation of STAT-1 on Ser-727 and expression of Fas/FasL in ventricular myocytes in the intact heart ex vivo. These results indicate that Fas/FasL genes and apoptosis are activated by STAT-1 in cardiac myocytes exposed to I/R and these effects are dependent on the Ser-727 but not the Tyr-701 phosphorylation sites of STAT-1.
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PMID:Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701. 1130 87

Protein kinase C (PKC)-mediated regulation of the mitogen-activated protein kinases (MAPK) may play a role in the protection afforded by ischemic preconditioning (PC). Nitric oxide (NO) can influence MAPK activation via interaction with PKC or farnesylation of low-molecular-weight (LMWT) G proteins. However, we have recently reported the mechanism of NO-induced cardioprotection to be a PKC-independent process. Therefore, we investigated the role of LMWT G proteins and MAPK signaling in NO-induced cardioprotection against simulated ischemia-reoxygenation (SI-R) injury. Neonatal rat cardiomyocytes treated for 90 min with the NO donor S-nitroso-N-acetyl-l,l-penicillamine (SNAP) 1 mM were protected against 6 h of SI (hypoxic conditions at 37 degrees C with 20 mM lactate, 16 mM KCl at pH 6.2) and 24 h reoxygenation under normal culture conditions. NO-induced protection was blocked by the G protein inhibitor alpha-hydroxyfarnesylphosphonic acid (alphaHFP) 10 microM. We studied the time course of p42/44 and p38 MAPK dual-phosphorylation hourly during SI using phospho-specific antibodies. p38 was phosphorylated during SI and the peak phosphorylation was significantly delayed by SNAP pretreatment. The p38 inhibitor SB203580 1 microM, given during SI, protected against injury. Thus the delay in peak p38 activation may contribute to, rather than be the effect of, NO-induced cardioprotection. We have shown that p38beta does not contribute to the total p38 signal in our extracts. Thus there is no detectable beta isoform. We conclude that the main isoform present in these cells and thought to be responsible for the observed phenomenon, is the alpha isoform.
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PMID:Role of G proteins and modulation of p38 MAPK activation in the protection by nitric oxide against ischemia-reoxygenation injury. 1152 99

Urocortin (UCN), is a peptide related to hypothalamic corticotrophin releasing hormone (CRF) and binds with high affinity to the CRF-R2 beta receptor which is expressed in the heart. UCN prevents cell death when administered to primary cardiac myocyte cultures both prior to simulated hypoxia/ischemia and at the point of reoxygenation after simulated hypoxia/ischemia as assayed by trypan blue exclusion. 3'-OH end labeling of DNA (TUNEL), annexin-V and fluorescence activated cell sorting. The protective effect of UCN is dependent on the p42/p44 mitogen-activated protein kinase (MAPK)-pathway. UCN also reduces damage in isolated rat hearts ex vivo, subjected to regional ischemia/reperfusion with the protective effect being observed when UCN is given either prior to ischemia or at the time of reperfusion after ischemia. Hence, UCN is a cardioprotective agent, which acts when given prior to ischemia or after ischemia at reperfusion.
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PMID:Urocortin protects against ischemic injury via a MAPK-dependent pathway. 1159 26


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