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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:363.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Platelet Activation by Low Concentrations of Intact Oxidized LDL Particles Involves the PAF Receptor

Rui Chen; Xi Chen; Robert G. Salomon; Thomas M. McIntyre

From the Department of Cell Biology (R.C., T.M.M.), Lerner Research Institute, Cleveland Clinic College of Medicine of Case Western Reserve University; and the Department of Chemistry (X.C., R.G.S.), Case Western Reserve University, Cleveland, Ohio.

Correspondence to Thomas M. McIntyre, Department of Cell Biology, NE-10, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, 9500 Euclid Ave, Cleveland, OH 44195. E-mail mcintyt{at}ccf.org

Objective— Mitochondrial depolarization aids platelet activation. Oxidized LDL (oxLDL) contains the medium length oxidatively truncated phospholipid hexadecyl azelaoyl-lysoPAF (HAz-LPAF) that disrupts mitochondrial function in nucleated cells, so oxLDL may augment platelet activation.

Methods and Results— Flow cytometry showed intact oxLDL particles synergized with subthreshold amounts of soluble agonists to increase intracellular Ca²⁺, and initiate platelet aggregation and surface expression of activated gpIIb/IIIa and P-selectin. oxLDL also induced aggregation and increased intracellular Ca²⁺ in FURA2-labeled cells by itself at low, although not higher, concentrations. HAz-LPAF, alone and in combination with substimulatory amounts of thrombin, rapidly increased cytoplasmic Ca²⁺ and initiated aggregation. HAz-LPAF depolarized mitochondria in intact platelets, but this required concentrations beyond those that directly activated platelets. An unexpectedly large series of chemically pure truncated phospholipids generated by oxidative fragmentation of arachidonoyl-, docosahexaneoyl-, or linoleoyl alkyl phospholipids were platelet agonists. The PAF receptor, thought to effectively recognize only phospholipids with very short sn-2 residues, was essential for platelet activation because PAF receptor agonists blocked signaling by all these medium length phospholipids and oxLDL.

Conclusions— Intact oxLDL particles activate platelets through the PAF receptor, and the PAF receptor responds to a far wider range of oxidized phospholipids in oxLDL than anticipated.

Oxidized LDL contains truncated phospholipids that depolarize mitochondria of nucleated cells, and mitochondrial depolarization aids platelet activation. Indeed, very low amounts of intact oxLDL particles activated platelets. However, the PAF receptor unexpectedly recognized medium length oxidized alkyl phospholipids, and oxidized LDL stimulates platelets via the PAF receptor, not mitochondrial damage.

Key Words: oxidized LDL • PAF • platelet • phospholipid • PAF acetylhydrolase

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