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 signaling pathway of cyclooxygenase-2 (COX-2) induction following ischemic preconditioning (IPC) in brain remains undefined. To determine role of COX-2 in ischemic preconditioning, we used two in vitro models: mixed cortical neuron/astrocyte cell cultures and organotypic hippocampal slice cultures. We simulated IPC by exposing cell or slice cultures to 1 h or 15 min of oxygen/glucose deprivation (OGD), respectively, 48 h prior to ischemia. To mimic ischemia in vitro, we exposed cell or slice cultures to OGD of 4 h or 40 min, respectively. In cell cultures, these experiments revealed that COX-2 induction peaked at 24 h following IPC in cell culture. Inhibition of COX-2 activation with 50 microM NS-398 (a COX-2 selective inhibitor) abolished IPC-mediated neuroprotection in both in vitro models. Next, we tested whether epsilon protein kinase C (epsilonPKC) and extracellular signal regulated kinase 1/2 (ERK1/2) activation was involved in IPC-mediated neuroprotection and COX-2 expression in cell culture. Cell cultures were treated with an epsilonPKC-specific activating peptide (psiepsilonRACK, 100 nM) for 1 h, and 48 h later were exposed to OGD. epsilonPKC activation increased ERK1/2 phosphorylation and COX-2 induction and conferred neuroprotection similar to IPC. Additionally, inhibition of either epsilonPKC or ERK1/2 activation abolished COX-2 expression and neuroprotection due to ischemic preconditioning. These results demonstrate a crucial role for the epsilonPKC-->ERK1/2-->COX-2 pathway in the induction of neuroprotection via ischemic preconditioning.
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PMID:Ischemic preconditioning via epsilon protein kinase C activation requires cyclooxygenase-2 activation in vitro. 1730 94

Activation of Na(+)/H(+) exchange (NHE) plays a major role in cell death following ischemia/hypoxia in many cell types, yet counteracts apoptotic cell death after other stimuli. To address the role of NHE activity in regulation of cell death/survival, we examined the causal relationship between NHE, p38 mitogen-activated protein kinase (MAPK), ERK1/2, p53, and Akt activity, and cell death, after chemical anoxia in NIH3T3 fibroblasts. The NHE1 inhibitor 5'-(N-ethyl-N-isopropyl) amiloride (EIPA) (5 muM), as well as removal of extracellular Na(+) [replaced by N-methyl-D: -glucamine (NMDG(+))], prevented recovery of intracellular pH (pH(i)) during chemical anoxia (10 mM NaN(3) +/- 10 mM glucose), indicating that activation of NHE was the dominating mechanism of pH(i) regulation under these conditions. NHE activation by chemical anoxia was unaffected by inhibitors of p38 MAPK (SB203580) and extracellular signal-regulated kinase (ERK) (PD98059). In contrast, chemical anoxia activated p38 MAPK in an NHE-dependent manner, while ERK1/2 activity was unaffected. Anoxia-induced cell death was caspase-3-independent, mildly attenuated by EIPA, potently exacerbated by SB203580, and unaffected by PD98059. Ser(15) phosphorylation of p53 was increased by anoxia in an NHE- and p38 MAPK-independent manner, while Akt activity was unaffected. It is suggested that after chemical anoxia in NIH3T3 fibroblasts, NHE activity is required for activation of p38 MAPK, which in turn protects the cells against anoxia-induced death. In spite of this, NHE inhibition slightly attenuates anoxia-induced cell death, likely due to the involvement of NHE in other anoxia-induced death pathways.
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PMID:Roles of Na+/H+ exchange in regulation of p38 mitogen-activated protein kinase activity and cell death after chemical anoxia in NIH3T3 fibroblasts. 1733 79

Elastin peptides (EPs) generated by hydrolysis of elastic fibers by elastinolytic enzymes display a wide spectrum of biological activities. Here, we investigated their influence on rat heart ischemia-mediated injury using the Langendorff ex vivo model. EPs, i.e., kappa elastin, at 1.32- and 660-nM concentrations, when administered before the ischemia period, elicited a beneficial influence against ischemia by accelerating the recovery rate of heart contractile parameters and by decreasing significantly creatine kinase release and heart necrosis area when measured at the onset of the reperfusion. All effects were S-Gal-dependent, as being reproduced by (VGVAPG)3 and as being inhibited by receptor antagonists, such as lactose and V14 peptide (VVGSPSAQDEASPL). EPs interaction with S-Gal triggered NO release and activation of PI3-kinase/Akt and ERK1/2 in human coronary endothelial cells (HCAECs) and rat neonatal cardiomyocytes (RCs). This signaling pathway, as designated as RISK, for reperfusion injury salvage kinase pathway, was shown to be responsible for the beneficial influence of EPs on ischemia/reperfusion injury on the basis of its inhibition by specific pharmacological inhibitors. EPs survival activity was attained at a concentration averaging that present into the blood circulation, supporting the contention that these matrikines might offer a natural protection against cardiac injury in young and adult individuals. Such protective effect might be lost with aging, since we found that hearts from 24-month-old rats did not respond to EPs.
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PMID:Binding of elastin peptides to S-Gal protects the heart against ischemia/reperfusion injury by triggering the RISK pathway. 1734 89

A variety of harmful stimuli, among them energy depletion occurring during transient brain ischemia, are thought to unbalance protein kinase cascades, ultimately leading to neuronal damage. In superfused, electrically stimulated rat cerebral cortex slices, chemical ischemia (CI) was induced by a 5-min treatment with the mitochondrial toxin, sodium azide (10 mM), combined with the glycolysis blocker, 2-deoxyglucose (2 mM). Thereafter, 1 h reperfusion (REP) with normal medium followed. Western blot analysis of p21Ras, extracellular signal-regulated protein kinases (ERK)1/2 (p44/42), phospho-ERK1/2, mitogen-activated protein kinase (MAPK)-p38, phospho-p38, stress-activated protein kinases/c-Jun NH2-terminal protein kinases (SAPK/JNK), phospho-SAPK/JNK was carried out. The level of p21Ras was increased by 40% immediately after CI, and did not return to control values following REP. Both ERK1 and ERK2 levels were reduced by CI and recovered to control values following REP; no significant change in their phosphorylation degree (phosphorylated to total level ratio, about 50% in the controls) was observed. Neither p38 levels, nor phosphorylation degree were changed following CI/REP. The activation of SAPK/JNK was significantly reduced under CI, and did not recover following REP. All CI/REP-induced effects were prevented by the NMDA receptor antagonist MK-801, 10 microM, suggesting the involvement of glutamate. The present findings show that although CI stimulates the p21Ras protein, MAPK levels and/or phosphorylation are reduced, possibly because of acute energy depletion. Because the activation of SAPK/JNK has been related to both apoptosis and neuroprotection, the decrease observed under CI/REP conditions may instead be related to nonapoptotic neuronal death. These results could be of interest in developing preventive treatments for ischemia/REP-induced brain damage.
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PMID:Effects of chemical ischemia on cerebral cortex slices: focus on mitogen-activated protein kinase cascade. 1738 88

Cellular prion protein (PrP(C)), a copper-binding glycosyl-phosphatidylinositol (GPI)-anchored membrane protein that is expressed predominantly in neurons can be induced in ischemia/hypoxic brain tissues. It was also found to be overexpressed and conferred multidrug resistance, promoting cancer metastasis and inhibiting apoptosis in gastric cancer in our lab. In solid tumors, hypoxia can promote malignant progression and confer resistance to chemotherapy by altering gene expression. In present study, we investigated the molecular mechanisms and signaling pathway involved in the induction of the PrP(C) gene by hypoxia in cancer cell lines. PrP(C) was detected to be upregulated in several cancer cell lines at both mRNA and protein level, and then found to be induced by hypoxia in a time-dependent manner. After hypoxia treatment, gastric cancer MKN28 cells transfected with luciferase reporter constructs of the human PrP(C) promoter, which contained HSE, expressed higher luciferase activities (4.3-fold) than those cells transfected with the constructs containing no HSE. In addition, the upregulation of PrP(C) was reduced by MERK/ERK inhibitor (PD98059). siRNA knockdown of PrP(C) could make the cells more sensitive to hypoxia induced drug sensitivity. In conclusion, from these findings, we can propose that some transcriptional factors phosphorylated by ERK1/2, could in turn interact with HSE in the promoter of PrP(C) resulting in upregulation of PrP(C) in gastric cancer cell line MKN28 during hypoxia. Downregulation of PrP(C) makes gastric cancer cells more sensitive to hypoxia induced drug sensitivity. However, other mechanisms might also be responsible for hypoxia induced overexpression of PrP(C) in gastric cancer.
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PMID:Hypoxia induced overexpression of PrP(C) in gastric cancer cell lines. 1738 71

The existing literature indicates a crucial role of p38 MAP (mitogen-activated protein) kinase (p38MAPK) and its downstream target MAPKAP kinase 2 (MK2) in ischemic preconditioning (IPC). Accordingly, deletion of MK2 gene should abolish the cardioprotective ability of IPC. Interestingly, we were able to partially precondition the hearts from MK2(-/-) knockout mice suggesting the existence of an as yet unknown alternative downstream target of p38MAPK. A recent study from our laboratory also determined a crucial role of CREB (cyclic AMP response element binding protein) in IPC. Since CREB is a downstream target of MSK-1 (mitogen- and stress-activated protein kinase-1) situated at the crossroad of ERK (extracellular receptor kinase) and p38MAPK signaling pathways, we reasoned that MSK-1 could be a downstream molecular target for p38MAPK and ERK signaling in the IPC hearts. To test this hypothesis, the rat hearts were subjected to IPC by four cyclic episodes of 5 min ischemia and 10 min reperfusion. As expected, IPC induced the activation of ERK1/2, p38MAPK, MK2 and HSP (heat shock protein) 27 as evidenced by their increased phosphorylation; and the inhibition of p38MAPK with SB203580 almost completely, and the inhibition of ERK1/2 with PD098059 partially, abolished cardioprotective effects of IPC. Inhibition of MSK-1 with short hairpin RNA (shRNA) also abolished the IPC-induced cardioprotection. SB203580 partially blocked the effects of MSK-1 suggesting that MSK-1 sits downstream of p38MAPK. shRNA-MSK-1 blocked the contribution of both p38MAPK and ERK1/2 as it is uniquely situated at the downstream crossroad of both of these MAP kinases. Although MSK-1 sits downstream of both ERK1/2 and p38MAPK, ERK1/2 activation appears to play less significant role compared to p38MAPK, since its inhibition blocked MSK activation only partially. Consistent with these results, shRNA-MSK-1 blocked the partial PC in MK2(-/-) hearts, and in combination with SB203580, completely abolished the PC effects in the wild-type hearts. The IPC-induced survival signaling was almost completely inhibited with SB203580, and only partially with PD 098059 as evidenced from the inhibition patterns of IPC induced activation of CREB, Akt and Bcl-2. Again SB203580 alone or in combination with shRNA-MSK-1 inhibited IPC induced survival signal comparatively, suggesting that MSK-1 exists downstream of p38MAPK. Taken together, these results indicate for the first time MSK-1 as an alternative (other than MK2) downstream target for p38MAPK, which also transmits survival signal through the activation of CREB.
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PMID:Ischemic preconditioning involves dual cardio-protective axes with p38MAPK as upstream target. 2323 Jun 4

Cardioprotection and preconditioning mediated via G-protein-coupled receptors may be lost or impaired with advancing age, limiting ischemic tolerance and the ability to pharmacologically protect older hearts from ischemic injury. Our preliminary findings indicated a loss of delta-opioid receptor-mediated protection in aged vs. young mouse hearts, which may involve alterations in protective kinase signaling. In the present study, we tested the hypothesis that aging-related loss of opioid-triggered cardioprotection involves failure to activate p38 MAPK and its distal signaling targets. Langendorff-perfused hearts from young (10-14 weeks) or aged (24-26 months) C57 mice underwent 25-min ischemia and 45-min reperfusion in the presence or absence of 1 micromol/l DPDPE (delta-opioid agonist) or 1 micromol/l anisomycin (activator of p38 MAPK), and functional recovery and protein activation/phosphorylation were assessed. Contractile recovery was similar in untreated young and aged hearts (50+/-2% and 53+/-5%, respectively), and was enhanced by DPDPE in young hearts only (67+/-3%). Immunoblot analysis revealed that DPDPE comparably activated or phosphorylated GRK2, Akt, ERK1/2 and p70S6 kinase in young and aged hearts, whereas aging abrogated the stimulatory effects of DPDPE on p38 MAPK and HSP27. Treatment with anisomycin elicited comparable activation of p38 MAPK and HSP27 in both young and aged hearts, coupled with a pronounced and equivalent cardioprotection in the two groups (73+/-3% and 77+/-2%, respectively), an effect abolished by the p38 MAPK inhibitor, SB203580. These data indicate that aging-related loss of delta-opioid-mediated cardioprotection involves failure to activate p38 MAPK and HSP27. Direct targeting of this pathway elicits comparable protection in both age groups.
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PMID:Impaired p38 MAPK/HSP27 signaling underlies aging-related failure in opioid-mediated cardioprotection. 1740 80

The specific delta-opioid receptor agonist [D-Ala(2)-D-Leu(5)]enkephalin (DADLE) protects against infarction in the heart when given before ischemia. In rabbit, this protection leads to phosphorylation of the pro-survival kinases Akt and extracellular signal-regulated kinase (ERK) and is dependent on transactivation of the epidermal growth factor receptor (EGFR). DADLE reportedly protects rat hearts at reperfusion. We therefore tested whether DADLE at reperfusion could protect isolated rabbit hearts subjected to 30 min of regional ischemia and 120 min of reperfusion and whether this protection is dependent on Akt, ERK, and EGFR. DADLE (40 nM) was infused for 1 h starting 5 min before reperfusion and reduced infarct size from 31.0 +/- 2.3% in the control group to 14.6 +/- 1.6% (P = 0.01). This protection was abolished by cotreatment of the metalloproteinase inhibitor (MPI) and the EGFR inhibitor AG1478. In contrast, 20 nM DADLE, although known to be protective before ischemia, failed to protect. Western blotting revealed that DADLE's protection was correlated to increase in phosphorylation of the kinases Akt and ERK1 and -2 in reperfused hearts (2.5 +/- 0.5, 1.6 +/- 0.2, and 2.3 +/- 0.7-fold of baseline levels, P < 0.05 vs. control). The DADLE-dependent increases in Akt and ERK1/2 phosphorylation were abolished by either MPI or AG1478, confirming a signaling through the EGFR pathway. Additionally, DADLE treatment increased phosphorylation of EGFR (1.4 +/- 0.2-fold, P = 0.03 vs. control). Thus the delta-opioid agonist DADLE protects rabbit hearts at reperfusion through activation of the pro-survival kinases Akt and ERK and is dependent on the transactivation of the EGFR.
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PMID:The delta-opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation. 1754 78

Anoxic preconditioning (APC) attenuates myocardial injury caused by ischemia/reperfusion. The protective mechanisms of APC involve up-regulation of the protective proteins and inhibition of apoptosis. 14-3-3 protein, as a molecular chaperone, plays an important role in regulating cell survival and apoptosis. However, the role of 14-3-3 protein in cardioprotection of APC and the pathways determining 14-3-3 protein expression during APC are not clear. In this work, Western blotting analysis was used to detect the 14-3-3 protein expression and activity of extracellular signal-regulated protein kinase 1/2 (ERK1/2) in cardiomyocytes subjected to anoxia-reoxygenation injury with and without APC and control. The cardiomyocytes from APC group were more resistant to injury induced by anoxia-reoxygenation and had much stronger phosphorylation of ERK1/2 than the control. The 14-3-3 protein expression was positively correlated with the phosphorylation of ERK1/2. Furthermore, inhibition of the ERK1/2 with PD98059 abolished the 14-3-3 protein up-regulation in cardiomyocytes induced by APC. The results indicate that APC up-regulates 14-3-3 protein expression through the ERK1/2 signaling pathways.
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PMID:Anoxic preconditioning up-regulates 14-3-3 protein expression in neonatal rat cardiomyocytes through extracellular signal-regulated protein kinase 1/2. 1762 8

Interleukin (IL)-6 family cytokines, which share glycoprotein 130 (gp130) as a signal-transducing receptor component, play important roles in the maintenance of cardiac homeostasis. IL-11, a member of IL-6 family cytokines, is expressed in cardiac myocytes, though it remains to be elucidated how IL-11 functions in the hearts. In the present study, first, we showed that IL-11 administration reduced the ischemia/reperfusion injury in the hearts. IL-11 receptor alpha was expressed in cardiomyocytes. IL-11 treatment rapidly activated signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) 1/2 in cardiac myocytes. IL-11 stimulation resulted in the translocation of phosphorylated STAT3 into nuclei. Immunofluorescence microscopic analyses revealed that IL-11 treatment led to the cell elongation, as is the case with other cardiotrophic members of IL-6 family, such as leukemia inhibitory factor. Finally we showed that IL-11 treatment conferred the resistance to cell death induced by hydrogen peroxide, which was abrogated by adenoviral transfer of dominant negative STAT3, but not by the inhibition of ERK1/2 with U0126. These findings indicate that IL-11 mediates cytoprotective signals in cardiomyocytes, proposing that IL-11 has the potential to exhibit cardioprotection as a novel biological function.
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PMID:Identification of cardiac myocytes as the target of interleukin 11, a cardioprotective cytokine. 1762 6


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