Comparison of 1-O-alkyl-, 1-O-alk-1'-enyl-, and 1-O-acyl-2-acetyl-sn-glycero-3-phosphoethanolamines and -3-phosphocholines as agonists of the platelet-activating factor family

O’Flaherty, Joseph T.; Tessner, Teresa G.; Greene, Dianne G.; Redman, J F; Wykle, Robert L.

doi:10.1016/0005-2760(94)90123-6

Cited by 29 publications

(8 citation statements)

References 40 publications

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“…In the positive ion mode, the product ion scan for (M+H) + at m/z 694 showed the ion pattern m/z 184, 104 and 86, which is typical for lipids containing phosphocholine (data not shown) [36]. …”

Section: Resultsmentioning

confidence: 99%

Structural Identification of Oxidized Acyl-Phosphatidylcholines That Induce Platelet Activation

et al. 2005

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Oxidation of low-density lipoprotein (LDL) generates proinflammatory and prothrombotic mediators that may play a crucial role in cardiovascular and inflammatory diseases. In order to study platelet-activating components of oxidized LDL 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine, a representative of the major phospholipid species in LDL, the 1-acyl-phosphatidylcholines (PC), was oxidized by CuCl₂ and H₂O₂. After separation by high-performance liquid chromatography, three compounds were detected which induced platelet shape change at low micromolar concentrations. Platelet activation by these compounds was distinct from the pathways stimulated by platelet-activating factor, lyso-phosphatidic acid, lyso-PC and thromboxane A₂, as evidenced by the use of specific receptor antagonists. Further analyses of the oxidized phospholipids by electrospray ionization mass spectrometry structurally identified them as 1-stearoyl-2-azelaoyl-sn-glycero-3-phosphocholine (m/z 694; SAzPC), 1-stearoyl-2-glutaroyl-sn- glycero-3-phosphocholine (m/z 638; SGPC), and 1-stearoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (m/z 622; SOVPC). These observations demonstrate that novel 1-acyl-PC which had previously been found to stimulate interaction of monocytes with endothelial cells also induce platelet activation, a central step in acute thrombogenic and atherogenic processes.

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Section: Resultsmentioning

confidence: 99%

Structural Identification of Oxidized Acyl-Phosphatidylcholines That Induce Platelet Activation

et al. 2005

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“…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 acid (8), the PAF receptor has two additional, important recognition requirements; one is for a specific headgroup, and the second is for a specific, atypical sn-2 residue.…”

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

184

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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“…Both PAFR-expressing and PAFRdeficient neurons are sensitive to the neurotoxic effects of PAF ligands (7,8), yet it is not clear whether these pathways are mediated by different PAF isoforms. PAFR recognizes glycerophospholipids with an sn-2 acetyl moiety and an sn-3 phosphocholine group (1,9). The length of the sn -2 carbon chain dictates PAFR affinity.…”

mentioning

confidence: 99%

“…Species with an sn -2 acetyl moiety exhibit the highest affinity (10)(11)(12). Substituting phosphoethanolamine for phosphocholine substantively reduces binding (9). The sn-1 ether linkage is not required for PAFR interaction but does increase potency several hundred-fold (1).…”

mentioning

confidence: 99%

Heterogeneity in the sn-1 carbon chain of platelet-activating factor glycerophospholipids determines pro- or anti-apoptotic signaling in primary neurons

Ryan

Harris

Carswell

et al. 2008

Journal of Lipid Research

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The platelet-activating factor (PAF) family of glycerophospholipids accumulates in damaged brain tissue following injury. Little is known about the role of individual isoforms in regulating neuronal survival. Here, we compared the neurotoxic and neuroprotective activities of 1-Ohexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C 16 -PAF) and 1-O-octadecyl-2-acetyl-sn-glycero-3-phosphocholine (C 18 -PAF) in cerebellar granule neurons. We find that both C 16 -PAF and C 18 -PAF cause PAF receptor-independent death but signal through different pathways. C 16 -PAF activates caspase-7, whereas C 18 -PAF triggers caspase-independent death in PAF receptor-deficient neurons. We further show that PAF receptor signaling is either pro-or anti-apoptotic, depending upon the identity of the sn-1 fatty acid of the PAF ligand. Activation of the PAF G-protein-coupled receptor (PAFR) by C 16 -PAF stimulation is anti-apoptotic and inhibits caspase-dependent death. Activation of PAFR by C 18 -PAF is pro-apoptotic. These results demonstrate the importance of the long-chain sn-1 fatty acid in regulating PAF-induced caspase-dependent apoptosis, caspase-independent neurodegeneration, and neuroprotection in the presence or absence of the PAF

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Comparison of 1-O-alkyl-, 1-O-alk-1'-enyl-, and 1-O-acyl-2-acetyl-sn-glycero-3-phosphoethanolamines and -3-phosphocholines as agonists of the platelet-activating factor family

Cited by 29 publications

References 40 publications

Structural Identification of Oxidized Acyl-Phosphatidylcholines That Induce Platelet Activation

Structural Identification of Oxidized Acyl-Phosphatidylcholines That Induce Platelet Activation

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

Heterogeneity in the sn-1 carbon chain of platelet-activating factor glycerophospholipids determines pro- or anti-apoptotic signaling in primary neurons

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