Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Our aim was to test the hypothesis that cardioprotection achieved with ischemic preconditioning (PC) involves increased activity of p38 mitogen-activated protein kinase (MAPK) early during sustained coronary artery occlusion. Using the isolated buffer-perfused rabbit heart model of regional ischemia, we quantified p38 MAPK activity (pmol/min/mg protein: by biochemical assay) at 5 and 10 min into coronary occlusion in hearts that first received PC ischemia or no intervention (controls), and in non-ischemic shams. Control hearts exhibited significant increases in p38 MAPK activity, averaging 883+/-142 and 1135+/-179 at 5 and 10 min of occlusion, v 144+/-49 in shams (P<0.05 and P<0.01). p38 MAPK activity was not, however, augmented with PC; rather, at 5 min into occlusion, activity was attenuated, averaging 432+/-72 (P=N.S. v sham). This early, modest reduction in p38 MAPK activity may be physiologically relevant: in additional hearts subjected to 30 min of sustained coronary occlusion and 2 h of reperfusion, infarct size (by tetrazolium staining: expressed as a % of the risk region) was 54+/-5% in hearts treated with SB 203580 (confirmed in our study to inhibit p38 MAPK activity at 5 min into occlusion) v 70+/-5% in vehicle controls (P<0.05). Thus, cardioprotection achieved with ischemic preconditioning in rabbit heart does not involve augmentation of p38 MAPK activity early during sustained coronary occlusion.
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PMID:p38 MAPK activity is not increased early during sustained coronary artery occlusion in preconditioned versus control rabbit heart. 1127 21

Minocycline, a semisynthetic tetracycline derivative, protects brain against global and focal ischemia in rodents. We examined whether minocycline reduces excitotoxicity in primary neuronal cultures. Minocycline (0.02 microm) significantly increased neuronal survival in mixed spinal cord (SC) cultures treated with 500 microm glutamate or 100 microm kainate for 24 hr. Treatment with these excitotoxins induced a dose-dependent proliferation of microglia that was associated with increased release of interleukin-1beta (IL-1beta) and was followed by increased lactate dehydrogenase (LDH) release. The excitotoxicity was enhanced when microglial cells were cultured on top of SC cultures. Minocycline prevented excitotoxin-induced microglial proliferation and the increased release of nitric oxide (NO) metabolites and IL-1beta. Excitotoxins induced microglial proliferation and increased the release of NO metabolites and IL-1beta also in pure microglia cultures, and these responses were inhibited by minocycline. In both SC and pure microglia cultures, excitotoxins activated p38 mitogen-activated protein kinase (p38 MAPK) exclusively in microglia. Minocycline inhibited p38 MAPK activation in SC cultures, and treatment with SB203580, a p38 MAPK inhibitor, but not with PD98059, a p44/42 MAPK inhibitor, increased neuronal survival. In pure microglia cultures, glutamate induced transient activation of p38 MAPK, and this was inhibited by minocycline. These findings indicate that the proliferation and activation of microglia contributes to excitotoxicity, which is inhibited by minocycline, an antibiotic used in severe human infections.
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PMID:Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. 1130 11

The spin trap alpha-phenyl-N-tert-butylnitron (PBN) is widely used for studies of the biological effects of free radicals. We previously reported the protective effects of PBN against ischemia-reperfusion injury in gerbil hippocampus by its activation of extracellular signal-regulated kinase (ERK) and suppression of both stress-activated protein kinase and p38 mitogen-activated protein kinase. In the present study, we found that PBN induced neurite outgrowth accompanied by ERK activation in PC12 cells in a dose-dependent manner. The induction of neurite outgrowth was inhibited significantly not only by transient transfection of PC12 cells with dominant negative Ras, but also by treatment with mitogen-activated protein kinase/ERK kinase inhibitor PD98059. The activation of receptor tyrosine kinase TrkA was not involved in PBN-induced neurite outgrowth. A protein kinase C (PKC) inhibitor, GF109203X, was found to inhibit neurite outgrowth. The activation of PKCepsilon was observed after PBN stimulation. PBN-induced neurite outgrowth and ERK activation were counteracted by the thiol-based antioxidant N-acetylcysteine. From these results, it was concluded that PBN induced neurite outgrowth in PC12 cells through activation of the Ras-ERK pathway and PKC.
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PMID:Induction of neurite outgrowth in PC12 cells by alpha -phenyl-N-tert-butylnitron through activation of protein kinase C and the Ras-extracellular signal-regulated kinase pathway. 1143 21

The activation of stress-activated protein (SAP) kinase may lead to an induction of apoptosis that is responsible for part of the cardiomyocyte death in reperfusion injury. The objective of the present study was to investigate the mechanism by which magnesium tanshinoate B (MTB), a bioactive compound isolated from Danshen, prevents apoptosis in cardiomyocytes in the ischemic/reperfused heart. Isolated adult rat hearts were perfused by the Langendorff mode with medium containing MTB prior to the induction of normothermic global ischemia. At the end of the 30-min ischemic period, the heart was reperfused with the same medium with or without MTB for an additional 20 min. In the MTB-treated ischemic/reperfused heart, the number of apoptotic nuclei was reduced by 2.5-fold in comparison to that in untreated ischemic/reperfused controls [23 +/- 4 vs 57 +/- 7 (mean +/- SD) TUNEL-positive cells, respectively, N = 3-4, P < 0.001]. SAP kinase activity was elevated 1.7-fold in ischemic/reperfused rat hearts [35.6 +/- 3.8 vs 21.2 +/- 3.3 (control) (mean +/- SEM) relative densitometric units, N = 4-6, P < 0.05]. Treatment with MTB abolished this elevation in SAP kinase activity (25.0 +/- 5.2 relative densitometric units), which was also decreased by 40% in the nucleus. When the heart was subjected to ischemia alone, there was no significant change in SAP kinase activity in the presence or absence of MTB. MTB did not appear to affect the p38 mitogen-activated protein kinase activity in this model system. In conclusion, MTB was shown to have cardioprotective activity against apoptosis, probably through the inhibition of SAP kinase activity.
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PMID:Inhibition of stress-activated protein kinase in the ischemic/reperfused heart: role of magnesium tanshinoate B in preventing apoptosis. 1144 59

We determined the role of p38 mitogen-activated protein kinase (MAPK), 72-kDa heat shock protein (HSP72), and antioxidant enzymes in whole body heat stress (HS)-induced cardioprotection in mouse hearts. Adult male mice were treated with either HS or anesthesia only. At 0.5, 48, 72, or 120 h later, the hearts were subjected to 20 min of global ischemia and 30 min of reperfusion in Langendorff mode. A significant protection against ischemia-reperfusion injury was observed 48 h after HS as demonstrated by: 1) reduction in infarct size; 2) decrease in leakage of lactate dehydrogenase; and 3) enhanced postischemic ventricular contractile function. No such protection was observed at other post-HS time points. HS caused an ~25% increase in phosphorylated c-Jun NH2-terminal kinase (JNK) but not p38 MAPK in the heart during the first 2-h post-HS time period. Cardioprotection was abolished by the MAPK inhibitor SB-203580, which also partially suppressed the HS-induced JNK phosphorylation. The protective effect was associated with a two- to threefold increase in HSP72 protein accumulation, but not antioxidant enzyme activities (catalase and Cu/Zn and Mn SOD) in the myocardium. Although HSP72 levels remained high 72 h after HS, the cardioprotection had already disappeared. We conclude that HS induces a transient delayed cardioprotection at 48 h after thermal stress in mice which appears to be mediated via a MAPK-signaling pathway.
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PMID:Mitogen-activated protein kinases mediate heat shock-induced delayed protection in mouse heart. 1145 53

The role of mitochondrial free radicals in the cardioprotective effect of ischemic preconditioning was examined in isolated buffer-perfused rat hearts. Infarct size in control rat hearts subjected to 30 min of regional ischemia and 120 min of reperfusion was 32.6 +/- 3.4% of the risk zone. Ischemic preconditioning (3 cycles of 5-min global ischemia/5-min reperfusion) before the same regional ischemia and reperfusion protocol significantly reduced infarct size to 2.6 +/- 0.8% of the risk zone. Perfusion with menadione (3.0 microM), a generator of mitochondrial free radicals, in lieu of preconditioning ischemia significantly reduced infarction to 10.9 +/- 2.7%. N-2-mercaptopropionylglycine (1.0 mM), a free radical scavenger, blocked the protection of menadione, significantly increasing infarction to 23.5 +/- 1.1%. Myxothiazol (0.6 microM), a site III mitochondrial inhibitor, blocked the protection of menadione and significantly increased infarction to 25.2 +/- 3.8%. The infarct-limiting effect of menadione was attenuated to 19.7 +/- 1.5% of the risk zone by 10 microM SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Furthermore, menadione significantly increased p38 MAPK phosphorylation to a level 5.6-fold over basal. These results indicate that free radicals that originate within mitochondria can activate p38 MAPK and protect hearts against infarction.
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PMID:Menadione mimics the infarct-limiting effect of preconditioning in isolated rat hearts. 1145 61

The expression of enzymes involved in fatty acid beta-oxidation (FAO), the principal source of energy production in the adult mammalian heart, is controlled at the transcriptional level via the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Evidence has emerged that PPARalpha activity is activated as a component of an energy metabolic stress response. The p38 mitogen-activated protein kinase (MAPK) pathway is activated by cellular stressors in the heart, including ischemia, hypoxia, and hypertrophic growth stimuli. We show here that PPARalpha is phosphorylated in response to stress stimuli in rat neonatal cardiac myocytes; in vitro kinase assays demonstrated that p38 MAPK phosphorylates serine residues located within the NH(2)-terminal A/B domain of the protein. Transient transfection studies in cardiac myocytes and in CV-1 cells utilizing homologous and heterologous PPARalpha target element reporters and mammalian one-hybrid transcription assays revealed that p38 MAPK phosphorylation of PPARalpha significantly enhanced ligand-dependent transactivation. Cotransfection studies performed with several known coactivators of PPARalpha demonstrated that p38 MAPK markedly increased coactivation specifically by PGC-1, a transcriptional coactivator implicated in myocyte energy metabolic gene regulation and mitochondrial biogenesis. These results identify PPARalpha as a downstream effector of p38 kinase-dependent stress-activated signaling in the heart, linking extracellular stressors to alterations in energy metabolic gene expression.
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PMID:p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response. 1157 87

The aim of the present study was to determine whether the attenuation of myocardial ischemic injury by SB203580 is due to the inhibition of p38 mitogen-activated protein kinase (MAPK) or to other documented nonspecific effects of the drug. We made adenoviral vectors encoding the alpha isoform of p38 MAPK with or without site-directed mutations to prevent SB203580 binding and inhibition. In embryonal rat heart-derived cells and adult rat cardiocytes expressing wild-type p38alpha MAPK, injury was reduced significantly by SB203580 present during simulated ischemia. In contrast, SB203580 did not protect cells expressing the SB203580-resistant form of p38alpha MAPK. These observations suggest that SB203580-mediated protection depends on the inhibition of p38alpha MAPK.
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PMID:Antiischemic effects of SB203580 are mediated through the inhibition of p38alpha mitogen-activated protein kinase: Evidence from ectopic expression of an inhibition-resistant kinase. 1167 3

beta-amyloid (A beta), derived form the beta-amyloid precursor protein (APP), is important for the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of A beta plaques and neurofibrillary tangles, and loss of neurons. However, introducing a human wild-type or mutant APP gene to rodent models of AD does not result in clear neurodegeneration, suggesting that contributory factors lowering the threshold of neuronal death may be present in AD. Because brain ischemia has recently been recognized to contribute to the pathogenesis of AD, we studied the effect of focal brain ischemia in 8- and 20-month-old mice overexpressing the 751-amino acid isoform of human APP. We found that APP751 mice have higher activity of p38 mitogen-activated protein kinase (p38 MAPK) in microglia, the main immune effector cells within the brain, and increased vulnerability to brain ischemia when compared with age-matched wild-type mice. These characteristics are associated with enhanced microglial activation and inflammation but not with altered regulation of cerebral blood flow, as assessed by MRI and laser Doppler flowmetry. Suppression of inflammation with aspirin or inhibition of p38 MAPK with a selective inhibitor, SD-282, abolishes the increased neuronal vulnerability in APP751 transgenic mice. SD-282 also suppresses the expression of inducible nitric-oxide synthase and the binding activity of activator protein 1. These findings elucidate molecular mechanisms of neuronal injury in AD and suggest that antiinflammatory compounds preventing activation of p38 MAPK in microglia may reduce neuronal vulnerability in AD.
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PMID:Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation. 1181 64

A direct role of carbon monoxide (CO), an effector-signaling molecule during heme oxygenase-1 (HO-1) catalysis of heme, in the protection against hepatic ischemia/reperfusion (I/R) injury needs to be established. This study was designed to determine the effects and downstream mechanisms of CO on cold I/R injury in a clinically relevant isolated perfusion rat liver model. After 24 hours of cold storage, rat livers perfused ex vivo for 2 hours with blood supplemented with CO (300 parts per million) showed significantly decreased portal venous resistance and increased bile production, as compared with control livers perfused with blood devoid of CO. These beneficial effects correlated with improved liver function (serum glutamic oxaloacetic transaminase levels) and diminished histological features of hepatocyte injury (Banff's scores). The CO-mediated cytoprotective effects were nitric oxide synthase- and cyclic guanine monophosphate-independent, but p38 mitogen-activated protein kinase (MAPK)-dependent. Moreover, adjunctive use of zinc protoporphyrin, a competitive HO-1 inhibitor, has shown that exogenous CO could fully substitute for endogenous HO-1 in preventing hepatic I/R insult. This study performed in a clinically relevant ex vivo cold ischemia model is the first to provide the evidence that HO-1-mediated cytoprotection against hepatic I/R injury depends on the generation of, and can be substituted by, exogenous CO. The p38 MAPK signaling pathway represents the key downstream mechanism by which CO prevents the I/R insult. In conclusion, regimens that employ exogenous CO should be revisited, as they may have potential applications in preventing/mitigating I/R injury, and thus expanding the liver donor pool for clinical transplantation.
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PMID:Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. 1191 27


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