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: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of different cell types to cooperate in the metabolism of reactive intermediates of arachidonic acid such as leukotriene A4 (LTA4) is currently receiving considerable attention. Of critical importance is the demonstration that transfer of LTA4 could occur under conditions when relatively low amounts of LTA4 are produced such as would be expected for in vitro receptor-mediated stimulation. Stimulation of human neutrophils with a combination of chemotactic factor (formyl-methionyl-leucyl-phenylalanine, FMLP) and phagocytosable particles (opsonized zymosan) resulted in little production of LTC4 alone, but measurable quantities appeared when platelets were coincubated. When these agonists were added to platelets alone in the absence of neutrophils, no LTC4 was produced. In the presence of stimulated neutrophils, the final synthesis of LTC4 was shown to occur within the platelets (from neutrophil-derived LTA4) by experiments using platelets that had been prelabeled with 35S-cysteine to label intracellular platelet glutathione. Other 35S-labeled sulfidopeptide leukotriene metabolites were also produced in this coincubation of neutrophils and platelets. The observed synergy between FMLP and opsonized zymosan in the production of LTC4 when neutrophils and platelets were coincubated may involve priming the neutrophil for LTA4 production. Activation of platelets or endothelial cells with thrombin did not alter the capacity of either cell to convert exogenously added LTA4 into LTC4. This would support the suggestion that even when platelets are activated they retain their capacity to metabolize LTA4 into LTC4. Finally, previous exposure of the platelets to LTA4 did not affect subsequent metabolism of arachidonic acid by the cyclooxygenase pathway to thromboxane A2 (TXA2) except at very high concentration of LTA4. These results suggest that cell-cell interactions may be critical determinants of the profile of eicosanoids produced in physiologic and pathophysiologic circumstances. In particular, we believe that both endothelial cells and platelets can, together with neutrophils, contribute relatively large amounts of sulfidopeptide leukotrienes to inflammatory and thrombotic events. These cell-cell interactions are aspirin-insensitive; therefore, aspirin-treated platelets are capable of synthesizing the vasoconstrictor LTC4 from neutrophil LTA4 at a time when they can no longer produce thromboxane.
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PMID:Transcellular biosynthesis of sulfidopeptide leukotrienes during receptor-mediated stimulation of human neutrophil/platelet mixtures. 222 31

We obtained evidence that the cyclooxygenase inhibitor d-indobufen, (+)2[p-(1-oxo-2-isoindolinyl)phenyl] buthylic acid has a potent and specific inhibitory effect on collagen-induced aggregation and 40K-protein phosphorylation (Mamiya, S., Hagiwara, M., Ishikawa, T., and Hidaka, H. Thromb. Res. 54, 447, 1989). In Fura-2 loaded platelets, d-indobufen inhibited collagen-induced intracellular calcium mobilization in a dose dependent manner and this inhibitory effect on calcium mobilization paralleled that on aggregation, either in the presence or absence of extracellular free calcium ions. This compound inhibited inositol phosphates (IPs) formation in collagen-stimulated platelets. In arachidonic acid-stimulated platelets, d-indobufen caused a lag on calcium mobilization, as observed with arachidonic acid-induced aggregation. There was no significant effect on thrombin- or A23187-induced calcium mobilization or on aggregation. These observations suggest that the collagen receptor couples to a distinct intracellular calcium mobilization system possibly via inositol phospholipid metabolism and that d-indobufen blocks the collagen-induced aggregation by arresting mobilization of intracellular calcium.
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PMID:d-Indobufen inhibits collagen-induced intracellular calcium mobilization and inositol phosphates formation in human platelets. 223 12

Certain arachidonic metabolites may play a pathogenic role in psoriasis. Platelets are rich sources of 12-hydroxy-eicosatetraenoic acid (12-HETE) and thromboxane A2, mediators of skin inflammation and platelet aggregation, respectively. We have studied untreated psoriatic patients without a history of diabetes mellitus and smoking. In psoriatics, platelet aggregation elicited by thrombin, ADP, and ristocetin was significantly enhanced as compared with healthy adult volunteers. Enhancement of platelet aggregation was detected in patients with both minimal and widespread disease. The formation of 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT), a cyclooxygenase product, and 12-HETE, a 12-lipoxygenase product, was increased in psoriatics with widespread disease but not in those with minimal disease. Formation of 12-HETE was stimulated to a higher degree (125%) than HHT (98%) in psoriasis (P less than 0.05). Addition of platelet-derived 12-HETE to cultured human epidermal keratinocytes resulted in a stimulation of the DNA synthesis (68% at 10(-7) M). These data suggest that platelet activation occurs in psoriasis, and that release of inflammatory and mitogenic compounds by activated platelets may play a role in the pathophysiology of psoriasis. Whether enhanced platelet aggregation in psoriasis is associated with occlusive vascular disease needs further investigation.
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PMID:Increased aggregation and arachidonic acid transformation by psoriatic platelets: evidence that platelet-derived 12-hydroxy-eicosatetraenoic acid increases keratinocyte DNA synthesis in vitro. 243 57

Experiments were designed to determine the role of the endothelial cells and the metabolism of arachidonic acid in anoxic contractions of isolated canine basilar arteries. Rings, with and without endothelium, of these arteries were suspended for isometric tension recording; anoxia was induced by switching the mixture gassing the organ chamber from 95% O2-5% CO2 to 95% N2-5% CO2. In rings with endothelium, anoxia evoked increases in tension under basal conditions and during contractions to 5-hydroxytryptamine, uridine triphosphate, prostaglandin F2 alpha, and high K+. Under control conditions, these anoxic contractions were not prevented by alpha-adrenergic and serotonergic antagonists, by apyrase, or by inhibitors of cyclooxygenase. Anoxia prevented endothelium-dependent relaxations evoked by vasopressin and thrombin. In rings without endothelium, anoxia caused increases in tension during contractions evoked by various agonists, and in unstimulated preparations after inhibition of cyclooxygenase. Anoxic contractions were abolished by calcium entry blockers. These observations suggest that anoxic contractions of isolated canine basilar artery can be explained by the release of endothelium-derived contracting factor(s) and the accelerated entry of calcium in the smooth muscle cells, which possibly results from a diversion of arachidonic acid from the cyclooxygenase to the lipoxygenase pathway.
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PMID:Anoxic contractions in isolated canine cerebral arteries: contribution of endothelium-derived factors, metabolites of arachidonic acid, and calcium entry. 243 36

To document further the involvement of external Ca2+ in the platelet-induced activation process, we have studied the arachidonate metabolism of intact washed rat platelets in the presence of different concentrations of Ca2+, Sr2+ or Ba2+. The thrombin-induced mobilization of radiolabeled arachidonate preincorporated into platelet phospholipids was followed as well as the subsequent formation of labeled cyclooxygenase and lipoxygenase products. Results indicate that upon thrombin stimulation (0.2 U/ml), the release of endogenous arachidonate and the formation of its metabolites are reduced by 50-90% only by omission of Ca2+ as compared to 1 mM Ca2+ in the suspending medium. At higher Ca2+ concentrations (5 mM), the arachidonate mobilization and metabolite formation are inhibited and the data are thus close to those obtained in the absence of Ca2+. In the presence of Sr2+ or Ba2+, the results indicate that these cations can substitute for Ca2+. As for Ca2+, an optimum concentration is found for Sr2+ and Ba2+ (3-5 mM), and higher concentrations inhibit the metabolism of arachidonic acid. As the above data might be compatible with the possible entry of Sr2+ and Ba2+ into platelets upon stimulation, we also studied the activity of a semi-purified preparation of phospholipase A2 from rat platelets. This activity was assayed (pH 9.2) using heat-denatured [3H]arachidonate-prelabeled phospholipids as substrate. The results show that this phospholipase A2 activity was strongly Ca2+-dependent. In addition, we found that unlike Mg2+, Sr2+ and Ba2+ are able to greatly enhance this activity. Relative efficiency (Vmax) was in the order Ca2+ greater than Sr2+ greater than Ba2+. Taken together, these findings suggest that external Ca2+ may play a major role in the regulation of rat platelet activity. Our interpretation is in line with the view that Sr2+ or Ba2+ could enter the platelet through a mechanism common to Ca2+ (a Ca2+ channel). Although direct evidence is awaited from the results of further studies which are in progress, it can reasonably be considered that Sr2+ or Ba2+ might cause platelet-induced activation mimicking a rise in the cytosolic Ca2+ and subsequent activation of Ca2+-dependent enzymes.
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PMID:Rat platelet arachidonate metabolism in the presence of Ca2+, Sr2+ and Ba2+: studies using intact platelets and semi-purified phospholipase A2. 244 63

The inhibitory effects of anion channel blockers were evaluated on aggregation, intracellular Ca2+ rises, and the production of arachidonic acid metabolites in human platelets. Inhibitors included five anion channel blockers: phloretin, probenecid, pyridoxal phosphate, 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS) and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS). The degree of inhibition by each of these agents was dose-dependent on thrombin-activated platelet function. These agents generally had no significant inhibitory effects on ionomycin-activated platelet functions. It is suggested that anion mobilization plays a major role in the receptor-mediated activation of platelet functions, but only a minor role in Ca2+ ionophore-induced platelet activation. It is also suggested that several agents may have properties unrelated to anion channel blockers. Phloretin may be a selective cyclooxygenase inhibitor, and probenecid may inhibit phospholipase A2. DIDS and SITS may interfere with certain aggregation-inducing mechanisms.
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PMID:Effects of five anion channel blockers on thrombin- and ionomycin-activated platelet functions. 247 40

The effect of the sulfhydryl (SH) group inhibitor ethylmercurithiosalicylate (thimerosal) on the function of human platelets was investigated. In contrast to known SH reagents such as p-chloromercuribenzoate or N-ethylmaleimide, thimerosal elicited both aggregation and [3H]serotonin release of washed human platelets at low micromolar concentrations (greater than or equal to 2 microM). Only a significant higher dose (greater than or equal to 15 microM) was effective when platelets were pretreated with the cyclooxygenase inhibitor aspirin, indicating an amplification of the proaggregatory effect of thimerosal by secondary prostaglandin (PG) endoperoxide and/or thromboxane (TX) formation. Consistent with this notion, thimerosal induced endogenous platelet arachidonic acid (20:4) metabolism which could be attributed to enhanced 20:4 liberation, presumably by activation of phospholipase A2. The latter effect was mediated by mobilization of intracellular calcium (Ca2+), and was not affected by removal of extracellular Ca2+. In the presence of aspirin, the thimerosal-induced Ca2+ elevation was completely reversed by dithiothreitol (DTT) which implicates SH groups in intracellular Ca2+ transport. In contrast to previous observations with other SH reagents, thimerosal had no effect on the inositoltrisphosphate (IP3)-mediated release or the sequestration (and/or extrusion) of intracellular Ca2+ following stimulation with thrombin, indicating an action on an as yet undefined CA2+ transport system.
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PMID:The sulfhydryl reagent thimerosal elicits human platelet aggregation by mobilization of intracellular calcium and secondary prostaglandin endoperoxide formation. 249 3

Pathways of arachidonic acid metabolism were identified in freshly prepared and in cultured bovine corneal endothelial cells. The principal pathway of arachidonic acid metabolism in the bovine corneal endothelial cells appears to be the cyclooxygenase pathway with the resultant synthesis of PGI2, PGF2 alpha and PGE2. At least two of these products, PGI2 and PGF2 alpha, are formed by the enzymatic conversion of the substrate, PGH2. Measurements of endogenous prostaglandin production by radioimmunoassay demonstrated that PGE2 was the major arachidonic acid metabolite released, with smaller amounts of PGF2 alpha and the stable hydrolysis product of PGI2, 6-keto PGF1 alpha. The release of all three prostanoids was significantly increased by the addition of the calcium ionophore (A23187), human thrombin, bradykinin and histamine. Basal and stimulated release of prostaglandins by the corneal endothelium may contribute to the regulation of intraocular pressure and also in the modulation of the corneal response to injury.
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PMID:Arachidonic acid metabolism by cultured bovine corneal endothelial cells. 249 58

Vasoconstrictor responses are augmented in porcine coronary arteries in hypercholesterolemia and atherosclerosis, leading to an occurrence of coronary vasospasm in the latter condition. The role of the endothelium in the vascular hyperreactivity in hypercholesterolemic and atherosclerotic coronary arteries was examined, particularly in response to aggregating and related vasoactive substances. Male Yorkshire pigs underwent balloon endothelial denudation of the left anterior descending coronary artery (LAD) and 2% high-cholesterol feeding for 10 weeks. Electron microscopic examination demonstrated a full lining of endothelial cells in the LAD and the left circumflex coronary artery (LCX). Endothelium-dependent responses were examined in vitro. In cholesterol-fed animals, endothelium-dependent relaxations to aggregating platelets, serotonin, ADP, bradykinin, thrombin, and the calcium ionophore A23187 were depressed in LAD (atherosclerosis), while the relaxations to aggregating platelets, serotonin and ADP were depressed in LCX (hypercholesterolemia). Serotonin-induced contractions were endothelium-dependently augmented in atherosclerotic LAD; the endothelium-dependent component of the contractions was inhibited by blockers of cyclooxygenase. Bioassay studies demonstrated a depressed release of endothelium-derived relaxing factor(s) from the atherosclerotic LAD in response to serotonin. These experiments indicate that the endothelium-dependent relaxations to aggregating platelets and related vasoactive substances are severely impaired in atherosclerosis and moderately impaired in hypercholesterolemia. Since coronary atherosclerosis was induced by a combination of balloon endothelial injury (and regeneration) and high-cholesterol feeding in this study, the combined effects of those factors must account for the severely impaired responses in atherosclerosis. The depressed release of the endothelium-derived relaxing factor(s) and the concomitant release of vasoconstrictor product(s) of cyclooxygenase appear to be responsible for the impaired relaxations.
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PMID:Impaired endothelium-dependent relaxation to aggregating platelets and related vasoactive substances in porcine coronary arteries in hypercholesterolemia and atherosclerosis. 249 69

Human umbilical vein endothelial cells convert linoleic acid to two monohydroxyoctadecadienoic (HODE) acids, 9- and 13-HODE. More 9-HODE than 13-HODE is formed under most conditions. The production of these metabolites is reduced substantially by acetylsalicylic acid, ibuprofen, or arachidonic acid, suggesting that cyclooxygenase may be involved in endothelial HODE synthesis. Incubations lasting up to 4 h indicate that the endothelial cells can convert [U-14C] linoleic acid into at least four additional products, some of which may be derived from the HODE that is formed initially. Radioactive 9- and 13-HODE are produced when the endothelial cells are labeled with linoleic acid and then exposed to thrombin, suggesting that these metabolites also may be formed when the endothelium is activated. If endothelial monolayers grown on micropore filters are incubated with linoleic acid, a substantial amount of the HODE formed accumulates in the basolateral fluid. This suggests that HODE may have extracellular effects, especially within the vascular wall. Furthermore, when 9- or 13-HODE are added, endothelial cultures produce less prostaglandin I2 and convert less 12-hydroxyeicosatetraenoic acid to its main metabolite, 8-hydroxyhexadecatrienoic acid. Therefore, in addition to extracellular actions, HODE also may have functional effects within the endothelium.
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PMID:Formation of 9-hydroxyoctadecadienoic acid from linoleic acid in endothelial cells. 249 21


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