Phospholipid Metabolism in Stimulated Human Platelets

Broekman, M. Johan; Ward, Jean W.; Marcus, Aaron J.

doi:10.1172/jci109854

Cited by 344 publications

(83 citation statements)

References 41 publications

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“…DG reached its peak concentration within 60s, accounting for 10-15% of the PI hydrolyzed, approximately the percentage that accumulates in response to thrombin (7,10). Both the dose-response and kinetic data presented are consistent with the findings of Broekman et al (27), monitoring PI hydrolysis under comparable conditions. In response to a 60-s exposure to 100 ug/ml collagen, platelets formed 1.7 nmol TXB2/2 X 109 platelets, and an equivalent amount of 12L-hydroxy-5,8,10-heptadecatrienoic acid (HHT), as gauged by radioactivity ( (Fig.…”

Section: Resultssupporting

confidence: 90%

“…As has been observed to be the case for thrombin-stimulated platelets (22), unhydrolyzed extracts accounted for most of the free myoinositol, implying that most of the myoinositol phosphate arising from the action of PLC had been digested by platelet phosphatases. PA, presumably derived via phosphorylation of DG, was observed in platelets exposed to collagen, as has been reported by Broekman et al (27). Treatment of platelets with aspirin before incubation with collagen inhibited the loss of PI, as we have noted already, as well as the formation of LPI, PA, and myoinositol.…”

Section: Resultssupporting

confidence: 89%

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Synergistic activation by collagen and 15-hydroxy-9 alpha,11 alpha-peroxidoprosta-5,13-dienoic acid (PGH2) of phosphatidylinositol metabolism and arachidonic acid release in human platelets.

Rittenhouse¹,

Allen²

1982

J. Clin. Invest.

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A B S T R A CT Collagen stimulates the activation of phosphatidylinositol (PI)-specific phospholipase C (EC 3.1.4.10) in human platelets, as manifested by the disappearance of PI, the transient formation of diacylglycerol (DG), and release of myoinositol. Platelets exposed to collagen also form lysophosphatidylinositol (LPI). Maximum formation of DG occurs within 60 s of the addition of collagen and is in proportion to the concentration of collagen provided, up to 100 Mg!2 X 109 platelets/ml. Hydrolysis of PI, formation of DG, and release of arachidonic acid are all inhibited -68% by aspirin or indomethacin, both of which inhibit platelet cyclooxygenase. This inhibition is reversed by the product of cyclooxygenase activity, 15-hydroxy -9a,lla -peroxidoprosta -5,13 -dienoic acid (PGH2), or by the PGH2 analogue and agonist, U-46619. The counteracting effects of either PGH2 or the PGH2 analogue can be blocked, in turn, by a PGH2 antagonist, U-51605. Neither PGH2 nor its stable analogue is, by itself, an efficient stimulus for PI breakdown to DG and LPI in platelets. However, in conjunction with collagen, these agents synergistically promote the net breakdown of PI and the release of arachidonic acid in aspirin-treated platelets. Our findings thereby imply that PGH2 has an important role in regulating both the release of its precursor, arachidonic acid, and the metabolism of PI induced by collagen.Dibutyryl cyclic AMP or prostaglandin D2 (PGD2), a prostaglandin that elevates concentrations of cAMP in platelets by stimulating adenylate cyclase, inhibits the hydrolysis of PI induced by collagen by 70%. The activation of PI metabolism by collagen appears to be

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 89%

Synergistic activation by collagen and 15-hydroxy-9 alpha,11 alpha-peroxidoprosta-5,13-dienoic acid (PGH2) of phosphatidylinositol metabolism and arachidonic acid release in human platelets.

Rittenhouse¹,

Allen²

1982

J. Clin. Invest.

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“…The hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2)' by phospholipase C is one of the earliest events known to occur when platelets are activated by agonists such as thrombin (1)(2)(3)(4). This process produced two key mediators of further platelet activation: diacylglycerol and inositol 1,4,5-triphosphate (IP3).…”

Section: Introductionmentioning

confidence: 99%

Inositol 1,4,5-triphosphate-induced granule secretion in platelets. Evidence that the activation of phospholipase C mediated by platelet thromboxane receptors involves a guanine nucleotide binding protein-dependent mechanism distinct from that of thrombin.

Brass¹,

Shaller²,

Belmonte³

1987

J. Clin. Invest.

160

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Phosphoinositide hydrolysis in platelets stimulated by thrombin is thought to be regulated by a pertussis toxin-sensitive guanine nucleotide binding protein (G protein) referred to as Gp. The present studies examine the role of GP in platelet responses to the thromboxane A2 analogue U46619 and in the pathway by which the phosphoinositide hydrolysis product inositol 1,4,5-triphosphate (IP3) causes secretion. In permeabilized platelets, U46619 caused phosphatidic acid formation and secretion, which were abolished by the G protein inhibitor, guanosine 5'-O(2-thiophosphate) (GDP,6S). Unlike thrombin, however, U46619-induced phosphoinositide hydrolysis was unaffected by pertussis toxin, and U46619 was unable to inhibit the I32PIADP ribosylation of the 42-kD pertussis toxin substrate in platelets. IP3-induced secretion, which is known to depend upon intracellular Ca release and subsequent arachidonic acid metabolism, was also inhibited by GDPj#S, as was Ca-induced secretion. These observations suggest (a) that platelet thromboxane A2 (TxA2) receptors are coupled to a toxin-resistant form of Gp distinct from the one that is coupled to thrombin receptors, and (b) that TxA2-stimulated phosphoinositide hydrolysis may serve as a feedback mechanism by which stimuli for arachidonic acid release, such as IP3 and Ca, amplify responses to agonists.

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“…We therefore suggest that both phospholipase A2 and phospholipase C are involved in the generation of arachidonic acid during phagocytosis in human polymorphonuclear cells. Finally, the simultaneous inhibition by quinacrine and IMX, inhibitors of the Ptdlns turnover (Lapetina & Cuatrecasas, 1979;Matsuzama & Hostetler, 1980;Brockman et al, 1980), of arachidonic acid generation and phagocytosis, indicate a function for this pathway during this process. Although arachidonic acid is the precursor of numerous metabolites, arachidonoyldiacylglycerol is a potential candidate to modulate protein kinase activity, as it has been shown in other systems.…”

Section: Specific Production Ofarachidonic Acid By Zymosanmentioning

confidence: 99%

Phospholipid turnover during phagocytosis in human polymorphonuclear leucocytes

Gil

Alonso

Chiva

et al. 1982

Biochemical Journal

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We have previously observed that the phagocytosis of zymosan particles coated with complement by human polymorphonuclear leucocytes is accompanied by a time-and dose-dependent inhibition of phosphatidylcholine synthesis by transmethylation [Garcia Gil, Alonso, Sanchez Crespo & Mato (1981) Biochem. Biophys. Res. Commun. 101, 740-7481. The present studies show that phosphatidylcholine synthesis by a cholinephosphotransferase reaction is enhanced, up to 3-fold, during phagocytosis by polymorphonuclear cells. This effect was tested by both measuring the incorporation of radioactivity into phosphatidylcholine in cells labelled with choline, and by assaying the activity of CDP-choline:diacylglycerol cholinephosphotransferase. The time course of CDP-choline:diacylglycerol cholinephosphotransferase activation by zymosan mirrors the inhibition of phospholipid methyltransferase activity previously reported. The extent of incorporation of radioactivity into phosphatidylcholine induced by various doses of zymosan correlates with the physiological response of the cells to this stimulus. This effect was specific for phosphatidylcholine, and phosphatidylethanolamine turnover was not affected by zymosan. The purpose of this enhanced phosphatidylcholine synthesis is not to provide phospholipid molecules rich in arachidonic acid. The present studies show that about 80% of the arachidonic acid generated in response to zymosan derives from phosphatidylinositol. A transient accumulation of arachidonoyldiacylglycerol has also been observed, which indicates that a phospholipase C is responsible, at least in part, for the generation of arachidonic acid. Finally, isobutylmethylxanthine and quinacrine, inhibitors of phosphatidylinositol turnover, inhibit both arachidonic acid generation and phagocytosis, indicating a function for this pathway during this process.PtdCho can be synthesized either by a cholinephosphotransferase reaction or by transmethylation. The first pathway involves the transfer of a phosphocholine group from CDP-choline to a 1,2-diacylglycerol molecule (Kennedy & Weiss, 1956). The second pathway involves the addition of three methyl groups into the amino group of a PtdEtn molecule, with S-adenosylmethionine as the methyl donor (Bremer & Greenberg, 1961). The purpose of these two pathways for PtdCho synthesis remains unclear. In rat hepatocytes cyclic AMP

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Phospholipid Metabolism in Stimulated Human Platelets

Cited by 344 publications

References 41 publications

Synergistic activation by collagen and 15-hydroxy-9 alpha,11 alpha-peroxidoprosta-5,13-dienoic acid (PGH2) of phosphatidylinositol metabolism and arachidonic acid release in human platelets.

Synergistic activation by collagen and 15-hydroxy-9 alpha,11 alpha-peroxidoprosta-5,13-dienoic acid (PGH2) of phosphatidylinositol metabolism and arachidonic acid release in human platelets.

Inositol 1,4,5-triphosphate-induced granule secretion in platelets. Evidence that the activation of phospholipase C mediated by platelet thromboxane receptors involves a guanine nucleotide binding protein-dependent mechanism distinct from that of thrombin.

Phospholipid turnover during phagocytosis in human polymorphonuclear leucocytes

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