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

Abstract

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 FeSO 4 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 Ca 2+ 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 Ca 2+ is absent. At >30% oxidation, p38 MAPK signaling increases further and is accompanied by Ca 2+ 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, α IIb β 3 . Conclusion— At >30% oxidation, LDL interferes with ligand binding to integrin α IIb β 3 , thereby attenuating platelet functions.