Platelet-aggregating effects of platelet-activating factor-like phosphollpids formed by oxidation of phosphatidylcholines containing an sn-2-polyunsaturated fatty acyl group

Tanaka, Tamotsu; Iimori, M; Tsukatani, Hiroaki; Tokumura, Akira

doi:10.1016/0005-2760(94)90122-8

Cited by 59 publications

(35 citation statements)

References 18 publications

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“…Because of the many products, it has been difficult to identify those that account for the bioactivity, especially when starting with a biologic source that contains a mixture of sn-1 bonds and various sn-2 fatty acyl residues. Further complicating the issue is the generation of PAF mimetics from synthetic diacyl phosphatidylcholines (12,16,17,39). These lack the sn-1 ether bond that confers potency, suggesting that an unusual modified sn-2 residue(s) produced by oxidative fragmentation might overcome the preference of the PAF receptor for an sn-1 ether bond.…”

Section: Discussionmentioning

confidence: 99%

“…The predominant biologic phosphatidylcholines are lipids of the diacyl subclass, and so the oxidation products are expected to be diacyl species. These oxidatively generated PAF analogs stimulate monocytes (15), leukocytes (16), and platelets (17). Oxidation of phosphatidylcholines to PAF-like lipids also occurs in vivo following exposure to the strong oxidant stress of cigarette smoke (15,18).…”

Section: Platelet-activating Factor (Paf)mentioning

confidence: 99%

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Inflammatory Platelet-activating Factor-like Phospholipids in Oxidized Low Density Lipoproteins Are Fragmented Alkyl Phosphatidylcholines

Marathe¹,

Davies²,

Harrison³

et al. 1999

Journal of Biological Chemistry

183

196

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Oxidation of human low density lipoprotein (LDL)generates proinflammatory mediators and underlies early events in atherogenesis. We identified mediators in oxidized LDL that induced an inflammatory reaction in vivo, and activated polymorphonuclear leukocytes and cells ectopically expressing human platelet-activating factor (PAF) receptors. Oxidation of a synthetic phosphatidylcholine showed that an sn-1 ether bond confers an 800-fold increase in potency. This suggests that rare ether-linked phospholipids in LDL are the likely source of PAF-like activity in oxidized LDL. Accordingly, treatment of oxidized LDL with phospholipase A 1 greatly reduced phospholipid mass, but did not decrease its PAF-like activity. Tandem mass spectrometry identified traces of PAF, and more abundant levels of 1-Ohexadecyl-2-(butanoyl or butenoyl)-sn-glycero-3-phosphocholines (C 4 -PAF analogs) in oxidized LDL that comigrated with PAF-like activity. Synthesis showed that either C 4 -PAF was just 10-fold less potent than PAF as a PAF receptor ligand and agonist. Quantitation by gas chromatographymass spectrometry of pentafluorobenzoyl derivatives shows the C 4 -PAF analogs were 100-fold more abundant in oxidized LDL than PAF. Oxidation of synthetic alkyl arachidonoyl phosphatidylcholine generated these C 4 -PAFs in abundance. These results show that quite minor constituents of the LDL phosphatidylcholine pool are the exclusive precursors for PAF-like bioactivity in oxidized LDL. Platelet-activating factor (PAF)1 is a phospholipid autacoid with a wide variety of actions, primarily on cells and events that comprise the inflammatory system. PAF initiates the rapid inflammatory response as it is the leukocyte activating molecule produced and displayed by stimulated endothelial cells (1). PAF does not induce the bactericidal effector functions of leukocytes, but rather stimulates their adhesive and migratory behavior that allows them to transit the endothelial barrier. Leukocytes (polymorphonuclear leukocytes or PMN), monocytes, and eosinophils, as well as platelets, express the PAF receptor and accordingly are activated by PAF in concentrations ranging from picomolar to nanomolar levels. The potency of PAF, its broad actions, and the potentially deleterious events it invokes rationalize the tight regulation of PAF synthesis (2).PAF is recognized by a single, specific receptor that is a member of the family of seven-transmembrane-spanning, Gprotein-linked receptors (3, 4). Alone among this large family of receptors and related orphan sequences, the PAF receptor recognizes an intact phospholipid, and does so with a marked specificity. The PAF receptor shows a several hundredfold selectivity for the sn-1 ether bond of PAF, and complete specificity for the sn-2 acetyl residue compared with the long chain fatty acyl residue of most alkyl phosphatidylcholines (5, 6). The choline headgroup confers a several thousandfold advantage over the related phosphatidylethanolamine analog (7). Thus, compared with Edg-2 and Edg-4 receptors for lysophosphatidic...

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Section: Discussionmentioning

confidence: 99%

Section: Platelet-activating Factor (Paf)mentioning

confidence: 99%

Inflammatory Platelet-activating Factor-like Phospholipids in Oxidized Low Density Lipoproteins Are Fragmented Alkyl Phosphatidylcholines

Marathe¹,

Davies²,

Harrison³

et al. 1999

Journal of Biological Chemistry

183

196

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“…corresponding oxidized I-acyl PCs, and that the activities of oxidized PCs were mainly due to MC-PCs. 7 ) From these findings, active components in the oxidized PCs were suggested to be MC-PCs formed from alkylacyl-GPC.…”

Section: Gc-ms Of P Af-like Phospholipids Formed During Peroxidation mentioning

confidence: 97%

“…Samples of 50 J.ll of the dispersion were added to 250 J.ll of a suspension of washed rabbit platelets, and platelet aggregation was monitored as described previously. 7) In some experiments, the platelets were treated with different concentrations of FR-900452 for I min before addition of the dispersion. The platelet-aggregating activities of the active phospholipid fractions were calculated as pmol equivalents of PAF (C I6 : 0 ) per I J.lmol of starting PC using a calibration curve for synthetic PAF (C 16 : 0 ).…”

Section: Fatty Acid Analysis Of 1-o-alkyl-2-acyl-g Pcmentioning

confidence: 99%

Platelet-activating Factor (PAF)-like Phospholipids Formed during Peroxidation of Phosphatidylcholines from Different Foodstuffs

Tanaka

Tokumura

Tsukatani

1995

Bioscience, Biotechnology, and Biochemistry

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“…In regard to the activating effect of PAF-like phospholipids via the PAF receptor on platelets [21][22][23], neutrophils [13], and monocytes [22], the general agreement are three-fold: First, 1-alkyl subclasses of PAF-like lipids were much potent activators than the corresponding 1-long chain acyl analogs. Second, the most potent group was MC-PC followed by HC-PC and DC-PC in both the sn-1-alkyl and acyl subclasses.…”

Section: Biological Effects Of Paf-like Phospholipidsmentioning

confidence: 99%

Generation of Platelet-Activating Factor (PAF)-Like Phospholipids in Blood Circulation under Elevated Oxidative Stress: Its Pathological Significance on Atherosclerosi

Tokumura¹,

Tuchie²,

Imasaki³

et al. 2004

J. Clin. Biochem. Nutr.

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Summary Oxidative modification of low-density lipoprotein (LDL) is known to be a critical factor for pathogenesis of atherosclerosis. Several newly generated lipid components in the oxidatively modified LDL (oxLDL) have been shown to exert undesirable effects on various vascular cells. In particular, phosphatidylcholine (PC) having an oxidatively shortened fatty acyl group with a methyl, hydroxyl, oxo or carboxyl terminal attained interest, since they mimic diverse effects of platelet-activating factor (PAF), a mediator of inflammation, owing to their structural analogy to PAF. In this article, generation of PAF-like lipids in response to elevated oxidative stress due to cigarette smoking is documented, and its possible significance on atherogenesis is discussed.

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Platelet-aggregating effects of platelet-activating factor-like phosphollpids formed by oxidation of phosphatidylcholines containing an sn-2-polyunsaturated fatty acyl group

Cited by 59 publications

References 18 publications

Inflammatory Platelet-activating Factor-like Phospholipids in Oxidized Low Density Lipoproteins Are Fragmented Alkyl Phosphatidylcholines

Inflammatory Platelet-activating Factor-like Phospholipids in Oxidized Low Density Lipoproteins Are Fragmented Alkyl Phosphatidylcholines

Platelet-activating Factor (PAF)-like Phospholipids Formed during Peroxidation of Phosphatidylcholines from Different Foodstuffs

Generation of Platelet-Activating Factor (PAF)-Like Phospholipids in Blood Circulation under Elevated Oxidative Stress: Its Pathological Significance on Atherosclerosi

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