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

Nicolaos Androulakis, Herve Durand, Ewa Ninio, and Demokritos C Tsoukatos

Department of Chemistry, University of Ioannina, Ioannina, Ioannina 45110

Corresponding Author: dtsoykat{at}cc.uoi.gr

Oxidation of LDL is thought to be involved in both initiating and sustaining atherogenesis through the formation of pro-inflammatory lipids and the covalent modification of LDL particles. Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent phospholipid mediator involved in inflammation. Upon oxidation of LDL, a large amount of oxidized phospholipids with PAF-like structure, is generated by fragmentation of the polyunsaturated fatty acyl moieties esterified at sn-2 position of glycerol. Some of the oxidatively generated PAF analogs may act via the PAF receptor. We evaluated the contribution of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) as well as of other PAF analogs, on the PAF-like bioactivity formed upon Cu2+-initiated oxidation of LDL. RP-HPLC purification, and ESI-MS analyses showed that upon oxidation of LDL, with inactivated PAF-acetylhydrolase, C16:0 PAF accounted for more than 30% of PAF-like biological activity and its sn-2 boutenoyl analogue for more than 50%. However upon LDL oxidation in the presence of exogenous lyso-PAF without PAF-acetylhydrolase inactivation, C16:0 PAF formation accounted for more than 90% of the biological activity recovered. We suggest, that the C16:0 PAF, despite being a minor constituent of the LDL peroxidation products, may substantially contribute 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 towards very short acyl chains (acetate (C2) vs boutanate (C4)), may explain the above contribution.

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