Synthesis and structure of the platelet aggregation factor thromboxane A2

Bhagwat, Shripad S.; Hamann, Philip R.; Still, W. Clark; Bunting, Stuart; Fitzpatrick, F. A.

doi:10.1038/315511a0

Cited by 135 publications

(52 citation statements)

References 23 publications

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“…14,15 Consistent with this suggestion is the fact that an inhibitor of PLA 2 prevented AR-induced platelet isoprostane and TxB 2 formation. Of note, 2 ROS scavengers, such as SOD and vitamin C, inhibited not only AR-induced isoprostane and TxB 2 production but also AR-induced NOX2 activation.…”

Section: Discussionsupporting

confidence: 67%

“…AR is associated in vitro and in vivo with enhanced formation of 2 platelet eicosanoids with proaggregating property, namely TxB 2 and isoprostanes. 14,15 Platelet TxB 2 formation after PCI despite concomitant low doses of aspirin suggests incomplete inhibition of platelet TxB 2 , which could favor post-PCI thrombotic complications. 19 Future studies should investigate whether a different therapeutic approach with aspirin may prevent PCI-induced platelet TxB 2 formation.…”

Section: Discussionmentioning

confidence: 99%

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Anoxia-Reoxygenation Enhances Platelet Thromboxane A ₂ Production via Reactive Oxygen Species–Generated NOX2

Basili

Pignatelli

Tanzilli

et al. 2011

ATVB

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Objective-Platelets undergoing anoxia-reoxygenation (AR) simultaneously increase reactive oxygen species (ROS) and thromboxane (Tx) B 2 . Our aim was to assess whether there is an interplay between activation of NOX2, the catalytic subunit of NADPH oxidase, and platelet TxB 2 in vitro and in vivo. Methods and Results-Platelets that underwent AR had enhanced ROS. This was associated with NOX2 activation and was inhibited by incubation with NOX2-blocking peptide. AR was associated with TxB 2 and isoprostane production, which were inhibited by NOX2-blocking peptide, vitamin C, and the inhibitor of phospholipase A 2 . Platelet incubation with 100 mol/L aspirin fully prevented AR-induced TxA 2 but did not affect isoprostane production. We included 56 aspirin-treated patients undergoing elective percutaneous coronary intervention (PCI) who were randomly allocated to receive either placebo or intravenous infusion of 1 g of vitamin C. Blood TxB 2 , isoprostanes, and soluble NOX2-derived peptide, a marker of systemic NADPH oxidase activation, significantly increased at 60 and 120 minutes after PCI in placebo-treated but not in vitamin C-treated patients. Conclusion-AR is associated with overproduction of platelet TxB 2 and isoprostanes, which is dependent on NOX2-dependent ROS generation. Low doses of aspirin are unable to prevent TxB 2 formation in patients who undergo PCI. Key Words: aspirin Ⅲ thromboxanes Ⅲ NOX2 Ⅲ vitamin C Ⅲ isoprostanes E xperimental models of ischemia-reperfusion are associated with a burst of reactive oxygen species (ROS), which may have deleterious effect in the coronary circulation. 1,2 Accordingly, percutaneous coronary intervention (PCI), a typical in vivo model of ischemia-reperfusion, has been associated with overproduction of isoprostanes, which are markers of oxidative stress, as well as with impaired microcirculatory flow. 3 Furthermore, in vitro experiments of anoxia-reoxygenation (AR) demonstrated enhanced platelet activation via formation of thromboxane (Tx) A 2 ; this may negatively influence the circulatory flow by predisposing to thrombotic complication. 4 AR-induced platelet TxB 2 formation follows arachidonic acid release by platelet membrane via ROS-induced phospholipase A 2 (PLA 2 ) activation. 5 However, the mechanism accounting for ROS formation in platelets undergoing AR is still undefined.NADPH oxidase, the most important cellular producer of ROS, is present not only in the immune innate cells but also in vessel walls and platelets. 6 Platelets express NOX2, the catalytic subunit of NADPH oxidase, along with the other cytosolic subunits. 7,8 Genetic deficiency of NOX2 is associated with low/absent platelet ROS formation and platelet dysfunction, thus suggesting that NOX2 activation is implicated in platelet activation and ROS formation. 9 We hypothesized that AR could enhance platelet TxB 2 formation via NOX2 activation and that antioxidants are able to prevent it. To this end, we analyzed in vitro whether NOX2 plays a role in the ROS formation elicited by AR and whether the...

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Anoxia-Reoxygenation Enhances Platelet Thromboxane A ₂ Production via Reactive Oxygen Species–Generated NOX2

Basili

Pignatelli

Tanzilli

et al. 2011

ATVB

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“…The of 20 sec at 0C and pH 7.4. This is substantially less stable than leukotriene A4 or thromboxane A2 (12,13), two of the most unstable of the evanescent family of products derived by oxygenation of polyunsaturated lipids. Our studies reported here are on the formation of allene oxides in flaxseed.…”

mentioning

confidence: 99%

Isolation and characterization of natural allene oxides: unstable intermediates in the metabolism of lipid hydroperoxides.

Brash

Baertschi²,

Ingram³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

119

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Allene oxides are unstable epoxides that have been implicated as intermediates in the biotransformation of hydroperoxyicosatetraenoic acids and related hydroperoxides to ketols and cyclopentenones. Direct proof of the structure of the putative allene oxide intermediates has been hampered by their extreme instability under the conditions of their biosynthesis (t½2 15-30 sec at 0C and pH 7.4). We now report the isolation and structural elucidation of allene oxides prepared from the (13S)-hydroperoxides of linoleic and linolenic acids. The compounds were biosynthesized by using a very active enzyme preparation from flaxseed. After a 5-sec incubation at 0C, the allene oxide metabolites were extracted and purified as the methyl ester derivatives at -15TC. The structures were established by UV, CD, NMR, and oxygen-18 labeling experiments. 12,13(S)-Oxido-9Z,11-octadecadienoic acid is derived from linoleic acid, and 12,13(S)-oxido-9Z,11,15Z-octadecatrienoic acid is from linolenic acid. Analysis of the breakdown products formed on exposure to water led to identification of hydrolysis and cyclization products previously characterized as enzymic derivatives of the (13S)-hydroperoxides in flaxseed. Our results give direct proof of the structure of the allene oxide intermediates and should facilitate further investigation of the metabolism of this class of epoxide to prostaglandins, clavulones, and other stable end products. tTo whom reprint requests should be addressed. 3382The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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“…TXA 2 is formed by the action of thromboxane synthase on the prostaglandin endoperoxide H 2 (PGH 2 ) and causes vasoconstriction, bronchoconstriction, and irreversible platelet aggregation (Hamberg et al, 1975;Svensson et al, 1976;Bhagwat et al, 1985;Fiddler and Lumley, 1990). Furthermore, recent studies have pointed out a significant stimulatory role of TXA 2 in the proliferation of vascular smooth muscle cells and mitogenesis (Pakala and Benedict, 1998;Koba et al, 2000).…”

mentioning

confidence: 99%

Pharmacological Characterization of N-tert-Butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A₂ Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bleeding Time

Dogné¹,

Hanson²,

Leval³

et al. 2004

J Pharmacol Exp Ther

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The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-NЈ-[2-(4Ј-methylphenylamino)-5-nitrobenzenesulfonyl]urea], an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor in rats, and to determine its effects on mice bleeding time. Intraperitoneal injection of a single dose of 5 mg/kg BM-573 to rats inhibited U-46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F 2 )-induced washed platelet aggregation 30 min and 1, 2, and 4 h after drug administration with a maximum antiplatelet effect observed after 1 and 2 h. In a rat model of thrombosis induced by ferric chloride application on the abdominal aorta, BM-573 significantly reduced the thrombus weight by 92.53, 80.20, 64.75, and 18.21% at doses of 5, 2, 0.5, and 0.2 mg/kg, respectively. Time to occlusion of abdominal aorta in the BM-573-treated group (41.50 Ϯ 5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16 Ϯ 0.79 min). Like furegrelate, seratrodast, and acetylsalicylic acid, BM-573 did not affect the tail bleeding time induced by tail transection in mice compared with vehicle-treated mice. Moreover, BM-573, a close derivative of the loop diuretic torasemide, failed to induce a significant increase in diuresis in rat and did not produce a decrease in blood glucose concentration as observed with the sulfonylurea glibenclamide. In conclusion, we have demonstrated that the nitrobenzenic sulfonylurea BM-573, an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor, is a potent antithrombotic agent that does not affect bleeding time. Moreover, BM-573 lost the diuretic property of torasemide and has no impact on glycemia.The isozymes cyclooxygenase (COX)-1 and -2 catalyze the conversion of arachidonic acid into thromboxane A 2 (TXA 2 ) and prostaglandins (PGs). The eicosanoid TXA 2 is the major COX-1 product of arachidonic acid metabolism in platelets.

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Synthesis and structure of the platelet aggregation factor thromboxane A2

Cited by 135 publications

References 23 publications

Anoxia-Reoxygenation Enhances Platelet Thromboxane A ₂ Production via Reactive Oxygen Species–Generated NOX2

Anoxia-Reoxygenation Enhances Platelet Thromboxane A ₂ Production via Reactive Oxygen Species–Generated NOX2

Isolation and characterization of natural allene oxides: unstable intermediates in the metabolism of lipid hydroperoxides.

Pharmacological Characterization of N-tert-Butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A₂ Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bleeding Time

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Synthesis and structure of the platelet aggregation factor thromboxane A2

Cited by 135 publications

References 23 publications

Anoxia-Reoxygenation Enhances Platelet Thromboxane A 2 Production via Reactive Oxygen Species–Generated NOX2

Anoxia-Reoxygenation Enhances Platelet Thromboxane A 2 Production via Reactive Oxygen Species–Generated NOX2

Isolation and characterization of natural allene oxides: unstable intermediates in the metabolism of lipid hydroperoxides.

Pharmacological Characterization of N-tert-Butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A2 Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bleeding Time

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Anoxia-Reoxygenation Enhances Platelet Thromboxane A ₂ Production via Reactive Oxygen Species–Generated NOX2

Anoxia-Reoxygenation Enhances Platelet Thromboxane A ₂ Production via Reactive Oxygen Species–Generated NOX2

Pharmacological Characterization of N-tert-Butyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A₂ Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bleeding Time