Identification of an enzyme in platelet microsomes which generates thromboxane A2 from prostaglandin endoperoxides

Needleman, Philip; Moncada, Salvador; Bunting, Stuart; Vane, John R.; Hámberg, Mats; Samuelsson, Bengt

doi:10.1038/261558a0

Cited by 504 publications

(197 citation statements)

References 18 publications

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“…The main source of TxA2 in the circulation is platelets (Needleman et al, 1976). Knauer et al (1981) and Gresele et al (1982) have shown that platelet activation is involved in allergic airway reactions.…”

Section: Plasma Txb2mentioning

confidence: 99%

Lung function and plasma levels of thromboxane B2, 6‐ketoprostaglandin F1 alpha and beta‐thromboglobulin in antigen‐induced asthma before and after indomethacin pretreatment.

Shephard¹,

Malan²,

Macfarlane³

et al. 1985

Brit J Clinical Pharma

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1 The effect of specific antigen challenge on the lung function of eight allergic asthmatic patients after placebo and indomethacin pretreatment has been investigated. 2 Plasma levels of thromboxane B2(TxB2), metabolite of thromboxane A2, 6-ketoPGFia, metabolite of epoprostenol, (prostacyclin, PGI2) and ,-thromboglobulin (,TBG) following antigen challenge in these eight patients have also been measured after placebo and indomethacin pretreatment. 3 Each patient underwent two antigen inhalations 1 week apart. One challenge took place after 4 days pretreatment with indomethacin capsules 25 mg four times daily, and the other took place following 4 days placebo pretreatment, one matched capsule four times daily. The order of administration was random but balanced and blind with respect to the patient. 4 Following placebo pretreatment two patients presented with an early antigen response only, four presented with a biphasic antigen response and two presented with a delayed antigen response only. The asthmatic response for each patient was consistent on reexposure. 5 Indomethacin pretreatment suppressed the delayed antigen induced asthmatic response. This suppression was reproducible. 6 There was a rise in plasma TxB2 levels on antigen challenge following placebo pretreatment but not following indomethacin pretreatment, whereas there was a rise in 6-keto-PGF1I after antigen challenge following indomethacin but not placebo pretreatment.7 No significant change in plasma ,BTBG or platelet counts from control values was observed following antigen challenge with either placebo or indomethacin pretreatment. 8 It is suggested that the production of PGI2 and suppression of TxA2 by indomethacin pretreatment contribute to the suppression of the delayed antigen induced asthmatic response and that platelets play a minimal role in this process.Keywords thromboxane B2 6-keto-prostaglandin Fla P-thromboglobulin platelets indomethacin antigen-induced asthma

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Section: Plasma Txb2mentioning

confidence: 99%

Lung function and plasma levels of thromboxane B2, 6‐ketoprostaglandin F1 alpha and beta‐thromboglobulin in antigen‐induced asthma before and after indomethacin pretreatment.

Shephard¹,

Malan²,

Macfarlane³

et al. 1985

Brit J Clinical Pharma

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“…The platelet provides a valuable cellular model for studying such prostaglandin receptors. The prostaglandin endoperoxides G2 and H2 are potent platelet stimulants (Hamberg et al, 1974;Willis et al, 1974), as is their major metabolic product, thromboxane A2 (Hamberg et al, 1975;Needleman et al, 1976). The study of these compounds is complicated by their lability in aqueous media, but analysis of their actions has been facilitated by the recent synthesis of stable analogues of prostaglandin H2 (Corey et al, 1975;Bundy, t Present address:…”

mentioning

confidence: 99%

Prostaglandin receptors on human platelets. Structure-activity relationships of stimulatory prostaglandins

MacIntyre¹,

Salzman²,

Gordon³

1978

Biochemical Journal

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1. Synthetic analogues of prostaglandins E2 or F2a, (monocyclic bisenoic prostaglandins), like the endogenous prostaglandin endoperoxides (prostaglandins G2 and H2) from platelets, and like synthetic analogues of prostaglandin H2 (bicyclic bisenoic prostaglandins), can induce aggregation of human platelets, although prostaglandins E2 and F2. themselves are inactive. 2. All the prostanoid compounds that induce platelet aggregation release 5-hydroxytryptamine from platelet dense bodies, but do not release f6-Nacetylglucosaminidase from lysosomal granules. Arachidonic acid evokes a similar response. 3. All endoperoxide analogues tested (bicyclic compounds) were powerful platelet stimulants, and all active compounds (whether mono-or bi-cyclic) apparently acted via the same receptor as the endogenous prostaglandin endoperoxides. 4. The nature and stereospecificity of substituents at positions 11 and 15 (or 16) on prostaglandin E2 are critical determinants for platelet-stimulating activity: deoxy substitution at position 11 plus methylation at position 15 (or 16) produces a potent stimulant, particularly if the groups around C-1 5 are in the S configuration. 5. The effects of these structural modifications are apparently due to, at least in part, a change in side-chain conformation.The formation of platelet aggregates and the associated secretion of platelet constituents, reactions of great importance in haemostasis and thrombosis, are influenced by prostaglandins and related compounds formed by the platelets in response to stimuli and also when these compounds are added exogenously (Kloeze, 1967;Willis, 1974;Samuelsson et al., 1976). The main precursor ofthe prostaglandins formed by most cell types (including platelets) is arachidonic acid, and its metabolic products have important and diverse effects on many cells, but with the notable exception of the corpus luteum (Powell et al., 1975), the receptors that mediate these effects have not yet been well characterized. The platelet provides a valuable cellular model for studying such prostaglandin receptors. The prostaglandin endoperoxides G2 and H2 are potent platelet stimulants (Hamberg et al., 1974;Willis et al., 1974), as is their major metabolic product, thromboxane A2 (Hamberg et al., 1975;Needleman et al., 1976). The study of these compounds is complicated by their lability in aqueous media, but analysis of their actions has been facilitated by the recent synthesis of stable analogues of prostaglandin H2 (Corey et al., 1975;Bundy, t Present address:

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“…Thromboxane A 2 (TXA 2 ) is generated from arachidonic acid by consecutive actions of cyclooxygenase (COX), existing as two isoforms of COX-1 and COX-2, and thromboxane synthase (TXAS) [1]. TXA 2 exhibits potent and diverse bioactivities, such as platelet…”

Section: Introductionmentioning

confidence: 99%

Activation of thromboxane receptor α induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells

Wei

Yan

et al. 2007

Biochemical Pharmacology

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Human lung adenocarcinoma A549 cells stably transfected with TPα (A549-TPα) were used to study agonist I-BOP-induced expression of cyclooxygenase-2 (COX-2) and the related mechanisms of induced expression. I-BOP, a TP agonist, induced a time and dose dependent expression of COX-2 in A549-TPα cells as revealed by Western blot and by the synthesis of PGE 2 and TXB 2 which was totally inhibited by COX-2 inhibitors. The signaling pathways of I-BOP-induced COX-2 expression were elucidated by using various inhibitors of the signaling molecules. The effects of these inhibitors were assessed at three different levels of COX-2 expression: protein, enzyme activity and promoter activity. Within MAPK family, both ERK and p38 MAPK but not JNK/SAPK pathways were involved in the induction. Other pathways such as JAK/Stat3 pathway and β-catenin/TCF/LEF pathway also participated in the induction. The activation of key signaling molecules, ERK, p38 MAPK, CREB and NF-κB, involved in the COX-2 transcription was further studied at the phosphorylation step. Activation of ERK and p38 MAPK appeared to be mediated primarily by transactivation of EGFR, whereas activation of CREB and NF-κB was mediated by PKA, PKC and ERK. The role of CREB and NF-κB in I-BOP-induced COX-2 expression was further explored at the COX-2 promoter level. Studies on promoter fragments of different length and mutation of responsive motifs indicated that CRE and NF-κB sites are critical for the COX-2 induction. Distal NF-κB site is essential for the basal induction of the COX-2 transcription, whereas CRE and proximal NF-κB sites are important for the induced transcription. These results indicate that I-BOP induced COX-2 expression through multiple signaling pathways leading to the activation of CREB and NF-κB transcriptional factors and subsequent COX-2 transcription.

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Identification of an enzyme in platelet microsomes which generates thromboxane A2 from prostaglandin endoperoxides

Cited by 504 publications

References 18 publications

Lung function and plasma levels of thromboxane B2, 6‐ketoprostaglandin F1 alpha and beta‐thromboglobulin in antigen‐induced asthma before and after indomethacin pretreatment.

Lung function and plasma levels of thromboxane B2, 6‐ketoprostaglandin F1 alpha and beta‐thromboglobulin in antigen‐induced asthma before and after indomethacin pretreatment.

Prostaglandin receptors on human platelets. Structure-activity relationships of stimulatory prostaglandins

Activation of thromboxane receptor α induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells

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