J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M500074-JLR200 on July 1, 2005

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Journal of Lipid Research, Vol. 46, 1923-1932, September 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Molecular and mechanistic characterization of platelet-activating factor-like bioactivity produced upon LDL oxidation

Nicolaos Androulakis*, Hervé Durand{dagger}, Ewa Ninio{dagger} and Demokritos C. Tsoukatos1,*

* Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
{dagger} Institut National de la Santé et de la Recherche Médicale U525, Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, 75 643 Paris, France

Published, JLR Papers in Press, July 1, 2005. DOI 10.1194/jlr.M500074-JLR200

1 To whom correspondence should be addressed. e-mail: dtsoykat{at}cc.uoi.gr

Oxidation of LDL is thought to be involved in both initiating and sustaining atherogenesis through the formation of proinflammatory lipids and the covalent modification of LDL particles. Platelet-activating factor (PAF; 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent phospholipid mediator involved in inflammation. Upon oxidation of LDL, oxidized phospholipids with PAF-like structure are generated, and some of them may act via the PAF receptor. We evaluated the contribution of 1-0-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) and of other PAF analogs on the PAF-like bioactivity formed upon Cu2+-initiated oxidation of LDL. Reverse-phase HPLC purification and electrospray ionization-MS analyses showed that upon oxidation of LDL with inactivated PAF-acetylhydrolase (PAF-AH), C16:0 PAF accounted for >30% of PAF-like biological activity and its sn-2 butenoyl analog accounted for >50%. However, upon LDL oxidation in the presence of exogenous 1-0-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) without PAF-AH inactivation, C16:0 PAF formation accounted for >90% of the biological activity recovered. We suggest that the C16:0 PAF, despite being a minor constituent of the LDL peroxidation products, may contribute substantially to the bioactivity formed in oxidized LDL.

The higher bioactivity of C16:0 PAF, and the higher selectivity of the LDL-attached lyso-PAF transacetylase toward very short acyl chains [acetate (C2) vs. butanate (C4)], may explain the contribution described above.

Abbreviations: acetyl-PC, 1-hexadecanoyl-2-acetyl-sn-glycero-3-phosphocholine; butanoyl-PAF, 1-0-hexadecyl-2-butanoyl-sn-glycero-3-phosphocholine; butanoyl-PC, 1-hexadecanoyl-2-butanoyl-sn-glycero-3-phosphocholine; butenoyl-PAF, 1-0-hexadecyl-2-butenoyl-sn-glycero-3-phosphocholine; CP, creatine phosphate; CPK, creatine phosphokinase; D3-PAF, 1-0-hexadecyl-2(D3)-acetyl-glycero-3-phosphocholine; ESI, electrospray ionization; lyso-PAF, 1-0-alkyl-sn-glycero-3-phosphocholine; C16:0 lyso-PAF, 1-0-hexadecyl-sn-glycero-3-phosphocholine; C16:0 lyso-PC, 1-hexadecanoyl-sn-glycero-3-phosphocholine; PAF, platelet-activating factor (1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine); C16:0 PAF, 1-0-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine; PAF-AH, platelet-activating factor-acetylhydrolase; PC, 1,2-diacyl-sn-glycero-3-phosphocholine; Pefabloc, 4-[2-aminoethyl]benzenesulfonyl fluoride; propionyl-PAF, 1-0-hexadecyl-2-propionyl-sn-glycero-3-phosphocholine; RP, reverse-phase

Supplementary key words oxidized phospholipids • platelet-activating factor-acetylhydrolase • platelet-activating factor-transacetylase • mediators of inflammation • atherogenesis • low density lipoprotein


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