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 current study focuses on the role of p38 MAP kinase in response to acute preconditioning stimuli and ischemia. Exposure of the rat myoblast cell line H9C2 to preconditioning stimuli, viz. brief duration of ischemia (metabolic inhibition) and adenosine, led to activation of p38 MAP kinase. The protective preconditioning effect of these stimuli against lethal ischemic insult was abolished in the presence or p38 MAP kinase inhibitor SB 203580 but not in the presence of MEK inhibitor PD 98509. Phorbol myristate acetate, PMA, which activates protein kinase C, PKC, activates p38 MAP kinase. and this activation is inhibited by PKC inhibitor G. 6850. The preconditioning effect of PMA was abolished by SB 203580 and also by protein kinase C inhibitor Go 6850. This indicates that the protective action of preconditioning by PKC is mediated via activation of p38 MAP kinase. Paradoxically, the presence of SB 203580 and Go 6850 during the lethal stress protected the cells against cell death. The mode of cell death in this study whether necrotic or apoptotic has not been established. Lethal ischemic stress activates p38 MAP kinase. Preconditioning the cells decreases the activation of p38 MAP kinase in response to the second lethal stress. These findings highlight the role of p38 MAP kinase in ischemic preconditioning v ischemia. Furthermore, our findings in an in vitro model using a proliferating cell line indicate that the duration and/or intensity of stimuli activating p38 kinase probably determines whether it would play a beneficial v deleterious role in cell survival in response to stress.
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PMID:Role of p38 MAP kinase in myocardial stress. 984 Dec 66

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

The MEK1 (MAP kinase/ERK kinase)/ERK (extracellular-signal-responsive kinase) pathway has been implicated in cell growth and differentiation [Seger, R. & Krebs, E. G. (1995) FASEB J. 9, 726-735]. Here we show that the MEK/ERK pathway is activated during focal cerebral ischemia and may play a role in inducing damage. Treatment of mice 30 min before ischemia with the MEK1-specific inhibitor PD98059 [Alessi, D. R., Cuenda, A., Cohen, P. , Dudley, D. T. & Saltiel, A. R. (1995) J. Biol. Chem. 270, 27489-27494] reduces focal infarct volume at 22 hr after ischemia by 55% after transient occlusion of the middle cerebral artery. This is accompanied by a reduction in phospho-ERK1/2 immunohistochemical staining. MEK1 inhibition also results in reduced brain damage 72 hr after ischemia, with focal infarct volume reduced by 36%. This study indicates that the MEK1/ERK pathway contributes to brain injury during focal cerebral ischemia and that PD98059, a MEK1-specific antagonist, is a potent neuroprotective agent.
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PMID:MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. 1053 14

Our previous studies suggested a protective role of the extracellular signal-regulated kinases (ERKs) cascade in ischemic preconditioning (IP) in the porcine heart. To test this hypothesis further, we studied the influence of the novel specific inhibitors of mitogen-activated protein kinase kinases (MEK 1/2) PD98059 (PD) and UO126 (UO) in IP. The substances were infused intramyocardially and UO also systemically in anesthetized, ventilated, open-chested, male pigs. The local intramyocardial PD and UO infusions occurred before IP and during both reperfusion (RP) phases of IP via four pairs of needles (three pairs verum, one solvent) into the risk area (RA). The IP design included two cycles of 10-min left anterior descending artery (LAD) occlusion and 10 min RP, followed by 40 min of occlusion (index ischemia) and of 60 min of RP. Biopsies of the areas of drug infusion were taken after the second RP cycle of IP. By Western blot analysis, the phosphorylation of ERK 1/2 and of the downstream transcription factor Elk-1 were measured, and the activities of the ERKs were tested by in gel phosphorylation. Only small infarcts were detected in the control group animals with the IP period [infarct size (IS), infarct area/risk area; IS, 2.5+/-0.1%]. Significant wedge-shaped infarcts were seen around the area of the PD and UO infusions. The effects of PD and UO were concentration dependent. The maximal dose of UO126 (7.5 mg systemically) was associated with an IS of 68.7+/-2.0%. At the end of IP, we observed a significant increase in phosphorylation and activities of ERKs. PD (50 microM) induced a 50% inhibition of ERK-1 and 56% of ERK-2 activities. Phosphorylated ERK-1 and ERK-2 were decreased after microinfusion of both PD and UO (50 microM). Microinfusion of 50 microM PD also significantly decreased the phosphorylation of Elk-1 (to 59.2+/-8.3% of control conditions). We demonstrate for the first time in vivo that the inhibition of ERKs by PD and UO results in a complete cancellation of IP.
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PMID:Inhibition of the ER-kinase cascade by PD98059 and UO126 counteracts ischemic preconditioning in pig myocardium. 1094 64

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

Opioids have been previously shown to confer acute and delayed cardioprotection against a prolonged ischemic insult. We have extensively characterized the signal transduction pathway mediating acute cardioprotection and have suggested a role for extracellular signal regulated kinase (ERK) in this cardioprotection. Therefore, we attempted to determine a role for ERK and the stress activated MAP kinase, p38, in opioid-induced delayed cardioprotection by using selective inhibitors of these pathways. All rats were subjected to 30 min of ischemia and 2 h of reperfusion (I/R). Control animals, injected with saline 48 h prior to I/R, had an infarct size/area at risk (IS/AAR) of 61.6 +/- 1.6.48-h pretreatment with TAN-67 (30 mg/kg), a delta1-opioid receptor agonist, maximally reduced IS/AAR (31.2 +/- 6.5). The involvement of ERK was examined with PD 098059, a selective pharmacological antagonist which inhibits the upstream kinase, MEK-1, that phosphorylates and activates ERK. PD 098059 (0.3 mg/kg) did not alter IS/AAR when administered alone (60.7 +/- 4.9). However, PD 098059 (0.3 mg/kg) administration 30 min prior to TAN-67 (30 mg/kg) completely abolished cardioprotection (61.0 +/- 7.6). The selective p38 inhibitor, SB 203580 (1.0 mg/kg), had no effect on IS/AAR in the absence of TAN-67 (53.1 +/- 2.3). Additionally, SB 203580 (1.0 mg/kg) when administered prior to TAN-67 (30 mg/kg) partially abolished cardioprotection (51.3 +/- 6.4). These results suggest that both ERK and p38 are integral components of opioid-induced delayed cardioprotection and may act via parallel pathways.
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PMID:ERK and p38 MAP kinase activation are components of opioid-induced delayed cardioprotection. 1132 31

Recent studies have provided evidence that Zn2+ plays a crucial role in ischemia- and seizure-induced neuronal death. However, the intracellular signaling pathways involved in Zn2+-induced cell death are largely unknown. In the present study, we investigated the roles of mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinase (JNK), p38 MAPK and extracellular signal-regulated kinase (ERK), and of reactive oxygen species (ROS) in Zn2+-induced cell death using differentiated PC12 cells. Intracellular accumulation of Zn2+ induced by the combined application of pyrithione (5 microM), a Zn2+ ionophore, and Zn2+ (10 microM) caused cell death and activated JNK and ERK, but not p38 MAPK. Preventing JNK activation by the expression of dominant negative SEK1 (SEKAL) did not attenuate Zn2+-induced cell death, whereas the inhibition of ERK with PD98059 and the expression of dominant negative Ras mutant (RasN17) significantly prevented cell death. Inhibition of protein kinase C (PKC) and phosphatidylinositol-3 kinase had little effect on Zn2+-induced ERK activation. Intracellular Zn2+ accumulation resulted in the generation of ROS, and antioxidants prevented both the ERK activation and the cell death induced by Zn2+. Therefore, we conclude that although Zn2+ activates JNK and ERK, only ERK contributes to Zn2+-induced cell death, and that ERK activation is mediated by ROS via the Ras/Raf/MEK/ERK signaling pathway.
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PMID:Zn2+-induced ERK activation mediated by reactive oxygen species causes cell death in differentiated PC12 cells. 1148 63

Brain subjected to acute ischemic attack caused by an arterial blockage needs immediate arterial recanalization. However, restoration of cerebral blood flow can cause tissue injury, which is termed reperfusion injury. It is important to inhibit reperfusion injury to achieve greater brain protection. Because oxidative stress has been shown to activate mitogen-activated protein kinases (MAPKs), and because oxidative stress contributes to reperfusion injury, MAPK may be a potential target to inhibit reperfusion injury after brain ischemia. Here, we demonstrate that reperfusion after forebrain ischemia dramatically increases phosphorylation level of extracellular signal-regulated kinase 2 (ERK2) in the gerbil hippocampus. In addition, i.v. administration of U0126 (100-200 mg/kg), a specific inhibitor of MEK (MAPK/ERK kinase), protects the hippocampus against forebrain ischemia. Moreover, treatment with U0126 at 3 h after ischemia significantly reduces infarct volume after transient (3 h) focal cerebral ischemia in mice. This protection is accompanied by reduced phosphorylation level of ERK2, substrates for MEK, in the damaged brain areas. Furthermore, U0126 protects mouse primary cultured cortical neurons against oxygen deprivation for 9 h as well as nitric oxide toxicity. These results provide further evidence for the role of MEK/ERK activation in brain injury resulting from ischemia/reperfusion, and indicate that MEK inhibition may increase the resistance of tissue to ischemic injury.
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PMID:Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia. 1157 56

Basic fibroblast growth factor (bFGF) is an important angiogenic factor produced by hearts subjected to ischemia. However, the direct effects of bFGF on myocardial cells are unknown. Primary cultured cardiac myocytes from neonatal rats were stimulated with lipopolysaccharide (LPS), a potent inducer of inducible nitric oxide synthase (iNOS), in the presence or the absence of bFGF. LPS induced the expression of iNOS in cardiac myocytes, demonstrated at both mRNA and protein levels. We showed that LPS activated the apoptotic pathway, evidenced by TUNEL staining, DNA ladder formation, and morphologic features. LPS-induced apoptosis was blocked by the administration of L-NAME, an inhibitor of NOS. This indicates that LPS induces apoptosis via an iNOS-dependent pathway. Administration of bFGF completely inhibited myocardial cell apoptosis induced by hydrogen peroxide or acidic medium as well as LPS. To determine signaling pathways for this inhibitory effect, we utilized PD098059, an MEK-1-specific inhibitor. PD098059 blocked bFGF-induced activation of ERK (extracellularly responsive kinase)-1/2 and neutralized the apoptotic inhibitory effect of bFGF. These findings demonstrate that LPS induces myocardial cell apoptosis in an iNOS-dependent manner. The results also suggest that bFGF is a protective factor against myocardial cell apoptosis and that this protection requires the MEK-1-ERK pathway.
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PMID:Basic fibroblast growth factor protects cardiac myocytes from iNOS-mediated apoptosis. 1180 11

Endothelial nitric oxide synthase (eNOS) is constitutively expressed in endothelial cells lining the blood vessel and the heart. It plays a major role in vascular and tissue protection. Its activity is tightly controlled by an intramolecular autoinhibitory element that hinders calmodulin binding. This molecular hindrance is removed by elevated intracellular calcium levels. The catalytic activity of eNOS is augmented by phosphorylation of a C-terminal serine residue (Ser-1177 of human eNOS) through the phosphatidyl-3 kinase (PI-3K)/Akt pathway. Its activity is also enhanced by binding to heat shock protein-90. These two processes are calcium independent. The two biochemical events appear to facilitate calmodulin access to its binding site. eNOS is upregulated at the transcriptional level. Its upregulation is mediated by an increased Sp1 binding to its cognate site on eNOS promoter/enhancer region via the action of protein phosphatase 2A (PP2A). PP2A is activated by a signaling pathway including PI-3gamma --> Janus activated kinase 2 (Jak2) --> MEK-1 --> ERK1 and 2. The transcriptional and posttranslational enhancement of eNOS activity is two- to threefold above the basal level. A higher magnitude of augmentation of eNOS gene expression can be achieved by gene transfer, which confers protection against vascular diseases and ischemia-induced tissue injury in experimental animals. These findings provide new insight into the protective role of eNOS and the therapeutic potential of eNOS gene therapy.
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PMID:Regulation of endothelial nitric oxide synthase activity and gene expression. 1207 69


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