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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:867.)
© 2005 American Heart Association, Inc.

Thrombosis

Effect of Oxidation on the Platelet-Activating Properties of Low-Density Lipoprotein

Suzanne J.A. Korporaal; Gertie Gorter; Herman J.M. van Rijn; Jan-Willem N. Akkerman

From the Thrombosis and Haemostasis Laboratory (S.J.A.K., G.G., J.-W.N.A.), Department of Haematology, and Department of Clinical Chemistry (H.J.M.R.), University Medical Center Utrecht, and the Institute for Biomembranes (S.J.A.K., G.G., J.-W.N.A.), University of Utrecht, the Netherlands.

Correspondence to Dr J. W. N. Akkerman, Thrombosis and Haemostasis Laboratory, G.03.647, Department of Haematology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, the Netherlands. E-mail j.w.n.akkerman{at}azu.nl

Objective— Because of the large variation in oxidizing procedures and susceptibility to oxidation of low-density lipoprotein (LDL) and the lack in quantification of LDL oxidation, the role of oxidation in LDL–platelet contact has remained elusive. This study aims to compare platelet activation by native LDL (nLDL) and oxidized LDL (oxLDL).

Methods and Results— After isolation, nLDL was dialyzed against FeSO₄ to obtain LDL oxidized to well-defined extents varying between 0% and >60%. The oxLDL preparations were characterized with respect to their platelet-activating properties. An increase in LDL oxidation enhances platelet activation via 2 independent pathways, 1 signaling via p38^MAPK phosphorylation and 1 via Ca²⁺ mobilization. Between 0% and 15% oxidation, the p38^MAPK route enhances fibrinogen binding induced by thrombin receptor (PAR-1)-activating peptide (TRAP), and signaling via Ca²⁺ is absent. At >30% oxidation, p38^MAPK signaling increases further and is accompanied by Ca²⁺ mobilization and platelet aggregation in the absence of a second agonist. Despite the increase in p38^MAPK signaling, synergism with TRAP disappears and oxLDL becomes an inhibitor of fibrinogen binding. Inhibition is accompanied by binding of oxLDL to the scavenger receptor CD36, which is associated with the fibrinogen receptor, _IIbß₃.

Conclusion— At >30% oxidation, LDL interferes with ligand binding to integrin _IIbß₃, thereby attenuating platelet functions.

OxLDL modulates platelet function via distinct mechanisms. At <15% oxidation, agonist-induced platelet functions are enhanced through activation of a p38^MAPK-mediated pathway. At >30% oxidation, oxLDL induces LPA-dependent Ca²⁺ mobilization, leading to immediate aggregation. At >15% oxidation, p38^MAPK-induced sensitization disappears and oxLDL inhibits agonist-induced platelet functions by binding to CD36, thereby interfering with _IIbß₃-mediated outside-in signaling.

Key Words: lipoproteins • platelets • oxidized LDL • scavenger receptor • lysophosphatidic acid

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