J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M700598-JLR200 on December 29, 2007

Papers In Press, published online ahead of print April 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700598-JLR200
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Journal of Lipid Research, Vol. 49, 832-846, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Polyunsaturated phospholipids promote the oxidation and fragmentation of {gamma}-hydroxyalkenals: formation and reactions of oxidatively truncated ether phospholipidsboxs

Xi Chen*, Wujuan Zhang*, James Laird*, Stanley L. Hazen{dagger},§,** and Robert G. Salomon1,*

* Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106
{dagger} Department of Cell Biology, Cleveland Clinic, Cleveland, OH 44195
§ Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195
** Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195

boxs The online version of this article (available at http://www.jlr.org) contains supplementary data.

Published, JLR Papers in Press, December 29, 2007.

1 To whom correspondence should be addressed. e-mail: rgs{at}po.cwru.edu

Low density lipoprotein contains traces of biologically active platelet-activating factor (PAF)-like ether phosphatidylcholines (PCs). These oxidatively truncated alkylacylphosphatidylcholines (OxPAFs) are presumably formed through the oxidative truncation of 1-alkyl-2-polyunsaturated fatty acyl PCs. We now report that a diverse structural variety of OxPAFs are generated in small unilamellar vesicles (SUVs) upon myeloperoxidase (MPO)-promoted autoxidation of ether PCs that incorporate linoleoyl, arachidonyl, or docosahexaenoyl groups at the sn-2 position. Total syntheses are reported that confirm the identities of the new OxPAFs and will facilitate the evaluation of their biologically important chemistry and activities. Especially noteworthy is the formation of OxPAFs containing {gamma}-hydroxyalkenal functionality. Analogous oxidatively truncated diacylphosphatidylcholines are biologically important because they and their more oxidized derivatives are strong ligands for the scavenger receptor CD36. Furthermore, their covalent adduction with proteins can interfere with protein function or generate biologically active carboxyalkylpyrrole derivatives. We now find a profound influence of membrane composition on the stability of OxPAFs. In the presence of a polyunsaturated diacyl PC, the linoleic acid ester of 2-lysophosphatidylcholine, MPO induces the oxidation of aldehydes to carboxylic acids and the further oxidative truncation of {gamma}-hydroxyalkenals. Remarkably, these reactions do not occur readily with MPO in SUVs composed entirely of saturated diacyl-PCs. A mechanistic rationale is presented that can account for this dichotomy.

Supplementary key words myeloperoxidase • platelet-activating factor • liquid chromatography-tandem mass spectrometry • low density lipoprotein

Abbreviations: AA, arachidonic acid; A-PAF, 1-O-hexadecyl-2-azeleyl-sn-glycero-3-phosphatidylcholine; AA-PAF, 1-O-hexadecyl-2-arachidonoyl-sn-3-phosphatidylcholine; CEP, carboxyethylpyrrole; DHA, docosahexaenoic acid; DHA-PAF, 1-O-hexadecyl-2-docosahexaenoyl-sn-3-phosphatidylcholine; G-PAF, 1-O-hexadecyl-2-glutaroyl-sn-glycero-3-phosphatidylcholine; HDdiA-PAF, 1-O-hexadecyl-2-(11-carboxy-9-hydroxyundec-10-enoyl)-sn-glycero-3-phosphatidylcholine; HHdiA-PAF, 1-O-hexadecyl-2-(7-carboxy-4-hydroxyhex-5-enoyl)-sn-glycero-3-phosphatidylcholine; HODA-PAF, 1-O-hexadecyl-2-(9-hydroxy-12-oxododec-10-enoyl)-sn-glycero-3-phosphatidylcholine; HOdiA-PAF, 1-O-hexadecyl-2-(5-hydroxy-7-carboxyhept-6-enoyl)-sn-glycero-3-phosphatidylcholine; HOHA-PAF, 1-O-hexadecyl-2-(4-hydroxy-7-oxohept-5-enoyl)-sn-glycero-3-phosphatidylcholine; HOOA-PAF, 1-O-hexadecyl-2-(5-hydroxy-8-oxooct-6-enoyl)-sn-glycero-3-phosphatidylcholine; KDdiA-PAF, 1-O-hexadecyl-2-(11-carboxy-9-oxoundec-10-enoyl)-sn-glycero-3-phosphatidylcholine; KHdiA-PAF, 1-O-hexadecyl-2-(6-carboxy-4-oxohex-5-enoyl)-sn-glycero-3-phosphatidylcholine; KODA-PAF, 1-O-hexadecyl-2-(9-oxo-12-oxododec-10-enoyl)-sn-glycero-3-phosphatidylcholine; KOdiA-PAF, 1-O-hexadecyl-2-(7-carboxy-5-oxohep-6-enoyl)-sn-glycero-3-phosphatidylcholine; KOHA-PAF, 1-O-hexadecyl-2-(4-oxo-7-oxohept-5-enoyl)-sn-glycero-3-phosphatidylcholine; KOOA-PAF, 1-O-hexadecyl-2-(5-oxo-8-oxooct-6-enoyl)-sn-glycero-3-phosphatidylcholine; LA, linoleic acid; LA-PAF, 1-O-hexadecyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine; LA-PC, linoleic acid ester of 2-lysophosphatidylcholine; lyso-PAF, 1-alkyl-2-hydroxy-sn-glycero-3-phosphocholine; MPO, myeloperoxidase; MRM, multiple reaction monitoring; OB-PAF, 1-O-hexadecyl-2-(4-oxobutyroyl)-sn-glycero-3-phosphatidylcholine; ON-PAF, 1-O-hexadecyl-2-(9-oxononanoyl)-sn-glycero-3-phosphatidylcholine; OV-PAF, 1-O-hexadecyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine; OxLDL, oxidized low density lipoprotein; OxPAF, oxidatively truncated alkylacylphosphatidylcholine; OxPC, oxidatively truncated diacylphosphatidylcholine; PAF, platelet-activating factor; PAFR, platelet-activating factor receptor; PC, phosphatidylcholine; S-PAF, 1-O-hexadecyl-2-succinoyl-sn-glycero-3-phosphatidylcholine; SUV, small unilamellar vesicle


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