Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the role of sphingolipids in regulating oxidant release in adherent human neutrophils. Stimulation of adherent neutrophils with formyl-Met-Leu-Phe (fMLP) resulted in the accumulation of ceramide at a time when H2O2 release is terminated. H2O2 release in fMLP-stimulated neutrophils was suppressed in a concentration-dependent manner by the exogenous addition of several free sphingoid amines and short chain ceramides. Sphingosine, dihydrosphingosine, phytosphingosine, N-acetylsphingosine, and N-acetylphytosphingosine, but not N-acetyldihydrosphingosine, inhibited formyl peptide-stimulated oxidant release. The half-maximal inhibitory concentrations of N-acetylsphingosine and N-acetylphytosphingosine were 0.51 and 0.38 microM, respectively. Sphingosine, dihydrosphingosine, and phytosphingosine were less potent inhibitors with half-maximal inhibitory concentrations of 1.78, 15.4, and 1.48 microM, respectively. The 4 beta-phorbol 12 beta-myristate 13 alpha-acetate-induced respiratory burst was inhibited by 5 microM of sphingosine but not by 5 microM of N-acetylsphingosine. The effects of N-acetyl-conjugated sphingols (C2 ceramides) on phosphatidylcholine-specific phospholipase D and phosphatidic acid phosphohydrolase were markedly different from the effects of the related sphingoid bases. Both C2 ceramides and sphingoid bases partially inhibited the diradylglycerol formation by the phosphatidylcholine-specific phospholipase D pathway. Under the same conditions, however, N-acetyldihydrosphingosine and dihydrosphingosine failed to suppress H2O2 release in fMLP-stimulated neutrophils. These findings demonstrate that C2 ceramides inhibit H2O2 generation in fMLP-stimulated neutrophils via protein kinase C- or sphingoid base-independent mechanisms. The effect of ceramide in inhibiting the respiratory burst is structurally specific, because either a 4,5-trans double bond or 4-hydroxyl group is required for the inhibition. Therefore, ceramides may regulate oxidant release in adherent neutrophils.
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PMID:Ceramide regulates oxidant release in adherent human neutrophils. 803 85

Reactive oxygen is an important regulator of vascular cell biology; however, the mechanisms involved in transducing signals from oxidants in endothelial cells are poorly defined. Because protein phosphorylation is a major mechanism for signal transduction, cultured aortic endothelial cells were exposed to nonlethal concentrations of H2O2 to examine oxidant-sensitive changes in phosphorylation state. Addition of H2O2 increases the phosphorylation of the heat shock protein 27 (HSP27) within 2 min. This response is maximal by 20 min and remains constant for more than 45 min. Levels of intracellular free Ca2+ in endothelial cells did not change following addition of 100 microM H2O2, nor did the ability of the cells to respond to bradykinin. H2O2-induced phosphorylations were either not affected or were slightly increased in cells pretreated with PKC inhibitors (H-8, staurosporin, or calphostin c). Two-dimensional analysis of phosphoproteins from homogenates of 32P-labeled cells revealed that phorbol myristate acetate (PMA) did not cause the same degree of HSP27 phosphorylation as H2O2. Simultaneous addition of 10 eta M PMA and 50 microM H2O2 decreased the oxidant-stimulated phosphorylation of the most acidic HSP27 isoform. These data suggest that signal transduction for H2O2-sensitive endothelial cell responses are not only independent of PKC, but may also be suppressed by the action of the kinase.
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PMID:Oxidant-sensitive protein phosphorylation in endothelial cells. 807 Jun 80

Activation of neutrophils may contribute to lung injury in the adult respiratory distress syndrome. We added rabbit neutrophils to the pulmonary circulation of salt-perfused and ventilated isolated rabbit lungs. These neutrophils were activated by adding synthetically pure melittin to the perfusate. This led to lung injury as measured by filtration coefficient under no-flow conditions. We also activated neutrophils in vitro before addition to the pulmonary circulation. These preactivated neutrophils also produced lung injury, indicating a primary action of melittin on neutrophils rather than on lung. The injury was prevented by aristolochic acid, which is an inhibitor of phospholipase A2 (PLA2), and independently by catalase, which is scavenger of hydrogen peroxide (H2O2). Aristolochic acid also appeared to act primarily on neutrophils since addition to neutrophils in vitro prevented injury from in vitro activation by melittin. Aristolochic acid did not appear to act as a free radical scavenger since it did not prevent injury from neutrophils activated by phorbol myristate acetate (PMA). PMA is a direct activator of protein kinase C in neutrophils and leads to formation of H2O2 with consequent lung injury. We conclude that activation of neutrophils by melittin leads to oxidant lung injury possibly from activation of PLA2. Since PLA2 does not directly produce a second messenger, such as diacylglycerol or inositol triphosphate, it is likely that other actions of PLA2 produce an intermediary mediator. We previously showed that an inhibitor of eicosanoid synthesis prevents lung injury from exogenous PLA2. This suggests that the formation of leukotriene B4 (LTB4), a 5-lipoxygenase product of arachidonic acid, may contribute to the oxidant lung injury from melittin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increase in filtration coefficient from actions of melittin on neutrophils in isolated rabbit lungs. 814 48

Platelets primed by exposure to subthreshold concentrations of arachidonic acid or collagen are known to be activated by nanomolar levels of hydrogen peroxide. We here demonstrate that this effect is mediated by hydroxyl radicals (OHzero) formed in an extracellular Fenton-like reaction. H2O2-induced platelet aggregation, serotonin release and thromboxane A2 productions were inhibited by OHzero scavengers and by the iron chelator desferrioxamine; hydroxyl radicals were detected directly by ESR measurements of the spin-trapped OHzero adduct. The role of OHzero was confirmed in experiments with exogenously added iron; free or EDTA-bound ferrous iron activated platelets in a process blocked by deoxyribose, mannitol or catalase, whereas ferric iron was without effect unless reductants were included. The activation by OHzero depended on concomitant release of arachidonic acid and was blocked by the phospholipase A2 inhibitors mepacrine and aristolochic acid, and by the Na+/K+ antiporter inhibitor ethylisopropylamiloride. In contrast, neomycin and staurosporin were without effects, indicating that phospholipase C and protein kinase C were not involved in the initial phase of activation. Neither radical formation nor arachidonic acid release was blocked by aspirin. In whole blood aggregation of platelets could be induced by H2O2 generated upon specific stimulation of neutrophils by N-formyl-methionyl-leucyl-phenylalanine; platelet activation and radical formation were blocked by the NADPH oxidase inhibitor diphenyliodonium as well as by catalase and mannitol. These results suggest that reactive oxygen species act as 'second messengers' during the initial phase of the platelet activation process.
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PMID:Role of hydroxyl radicals in the activation of human platelets. 817 49

To characterize the perioperative alterations in polymorphonuclear leukocytes (PMN) function mediated by protein kinase C, we studied twenty six patients undergoing gastrointestinal surgery. Seventeen patients with thoracic esophageal cancer were underwent total thoracic esophagectomy through a right thoracotomy (severe surgical stress group). Nine patients underwent cholecystectomy (slight surgical stress group). Measurement of O2- production capacity was used as a reflection of the activity of NADPH oxidase, and the activity of myeloperoxidase-H2O2-halide system was evaluated using luminol-dependent chemiluminescence. O2- production stimulated by phorbol 12-myristate 13-acetate (PMA) was suppressed, reaching a minimum on POD 3. On the other hand, luminol dependent chemiluminescence increased significantly after surgery, reached a maximum on POD 3. These alterations were more remarkable in the severely stressed patients. These results suggest that postoperative PMN signal transduction mechanisms, mediated by protein kinase C, may activate myeloperoxidase-H2-O2-halide system but suppress NADPH oxidase system dependently of the degree of surgical stress, revealing a differential effect of protein kinase C activation on PMN microbicidal activity.
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PMID:[Perioperative alterations in polymorphonuclear leukocyte function mediated by protein kinase C]. 817 96

Cells adapt to adverse environmental conditions through a wide range of responses that are conserved throughout evolution. Physical agents such as ionizing radiation are known to initiate a stress response that is triggered by the recognition of DNA damage. We have identified a signaling pathway involving the activation of phospholipase A2 and protein kinase C in human cells that confers x-ray induction of the tumor necrosis factor alpha gene. Treatment of human cells with ionizing radiation or H2O2 was associated with the production of arachidonic acid. Inhibition of phospholipase A2 abolished radiation-mediated arachidonate production as well as the subsequent activation of protein kinase C and tumor necrosis factor alpha gene expression. These findings demonstrate that ionizing radiation-mediated gene expression in human cells is regulated in part by extranuclear signal transduction. One practical application of phospholipase A2 inhibitors is to ameliorate the adverse effects of radiotherapy associated with tumor necrosis factor alpha production.
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PMID:Membrane-derived second messenger regulates x-ray-mediated tumor necrosis factor alpha gene induction. 819 53

A major goal of this work was to determine in NIH 3T3 fibroblasts whether the recently described effects of H2O2 on phospholipase D-mediated hydrolysis of phosphatidylethanolamine (PtdEtn) and phosphatidylcholine (PtdCho) are mediated by similar or different mechanisms. While exposure of NIH 3T3 fibroblasts to H2O2 stimulated the hydrolysis of both PtdEtn and PtdCho, the following important differences were noted: (i) prolonged (24 h) treatment of fibroblasts with 400 nM phorbol 12-myristate 13-acetate (PMA) blocked the stimulatory effect of H2O2 on PtdEtn, but not on PtdCho, hydrolysis; (ii) PMA-induced hydrolysis of PtdEtn, but not PtdCho, was inhibited by H2O2; (iii) the stimulatory effect of H2O2 was additive with that of sphingosine or staurosporine, inhibitors of protein kinase C, on the hydrolysis of PtdCho, but not PtdEtn; (iv) with membranes isolated from H2O2-treated fibroblasts, the hydrolysis of PtdCho, but not PtdEtn, was increased compared to values obtained with control membranes. These results imply that H2O2 regulates PtdEtn and PtdCho hydrolysis by different mechanisms. Stimulation of PtdEtn hydrolysis by H2O2, sphingosine, and staurosporine may commonly involve, at least in part, neutralization of an inhibitory protein kinase C isozyme.
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PMID:Hydrogen peroxide regulates phospholipase D-mediated hydrolysis of phosphatidylethanolamine and phosphatidylcholine by different mechanisms in NIH 3T3 fibroblasts. 820 6

The influence of oxidative stress on agonist-stimulated changes of intracellular free calcium and inositol trisphosphate in the neurosecretory PC12 cell line was investigated. The oxidant H2O2 modulated the bradykinin-induced calcium signal by decreasing the initial peak and the plateau phase in the same manner as tetraphorbolacetate, an activator of protein kinase C. Inositol trisphosphate formation, induced by bradykinin was also decreased by oxidative stress. Thiol protecting agents were able to restore the altered signal. In contrast to this, radical quenching substances had no influence on calcium signals in stressed cells. Inhibitors of several protein kinases, such as protein kinase C, protein kinase A, or cyclic GMP-dependent protein kinase showed the ability to protect the plateau phase of calcium signals against oxidative stress, but not the peak response. These results indicate that under the influence of oxidative stress multiple targets within the signal transduction cascades are affected.
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PMID:Modulation of bradykinin-induced calcium signals by oxidative stress in PC12 cells. 821 40

The aim of this study was to investigate the stimulating effects of sulfhydryl reagents on glucose transport in isolated rat heart muscle cells and to compare them with the action of insulin. Low concentrations of the sulfhydryl oxidants hydrogen peroxide (H2O2) and diamide (5-100 microM), but also of phenylarsine oxide (PAO) (0.5-3 microM), that is known to specifically react with vicinal SH-groups, stimulated the rate of 2-deoxy-D-glucose uptake by a factor of 4 to 8 in these cells, while higher concentrations were inhibitory. The stimulating effects of H2O2 or diamide, and, to a significantly lesser extent, those of PAO or insulin, were depressed in cells pretreated with the sulfhydryl-alkylating agent N-ethylmaleimide (56-100 microM). H2O2 raised the Vmax and lowered the Km of 3-O-methyl-D-glucose uptake, while PAO or insulin solely increased Vmax. The increase in glucose transport caused by H2O2 was antagonized by the beta-adrenergic agonist isoprenaline (1 microM) or by a membrane-permeant cyclic AMP analog, whereas the effects of PAO or insulin were not altered. The action of H2O2 was additive with the stimulation induced by the protein phosphatase inhibitors okadaic acid (1 microM) or vanadate (6 mM), whereas the responses to PAO or insulin were reduced in the presence of these agents. Finally, H2O2 and PAO, but not insulin, acted additively with the protein kinase C ligand phorbol myristate acetate (0.8 microM) and with phospholipase C (0.03 units/ml). We conclude that, in cardiac myocytes, H2O2, on the one hand, and PAO (and possibly insulin), on the other hand, stimulate glucose transport via at least two distinct, SH-dependent pathways. These pathways, in turn, differ from a protein kinase C- and from a phospholipase C-mediated mechanism.
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PMID:Phenylarsine oxide and hydrogen peroxide stimulate glucose transport via different pathways in isolated cardiac myocytes. 824 Dec 56

The present study was undertaken to test the hypothesis that activation of cell membrane associated protein kinase C (PKC) plays a role in stimulating cell membrane associated phospholipase A2 (PLA2) activity, and subsequent liberation of arachidonic acid (AA) under exposure of rabbit pulmonary arterial smooth muscle cells to the oxidant hydrogen peroxide (H2O2). Exposure of the smooth muscle cells to H2O2 dose-dependently stimulates [14C] AA release, and enhances the cell membrane associated PLA2 activity. Pretreatment of the cells with protein kinase C (PKC) inhibitors H7 and sphingosine prevent the cell membrane associated PLA2 activity, and AA release caused by H2O2. Treatment of the smooth muscle cells with H2O2 stimulates the cell membrane associated PKC activity. Pretreatment of the cells with an antioxidant vitamin E prevents H2O2 caused stimulation of the cell membrane associated PKC activity. The cell membrane associated PLA2 and PKC activities correlate linearly. These results suggest that H2O2 caused stimulation of the smooth muscle cell membrane associated PLA2 activity, and subsequent liberation of AA can occur through an increase in the activity of the cell membrane associated PKC.
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PMID:Role of protein kinase C in oxidant--mediated activation of phospholipase A2 in rabbit pulmonary arterial smooth muscle cells. 835 Aug 69


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