Platelet activation by low concentrations of intact oxidized LDL particles involves the PAF receptor.
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.


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.
Chen
Rui
R
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
Chen
Xi
X
Salomon
Robert G
RG
McIntyre
Thomas M
TM
D000244:Adenosine Diphosphate / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D010742:Phospholipid Ethers / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D008024:Ligands; D008077:Lipoproteins, LDL; D019007:P-Selectin; D010742:Phospholipid Ethers; D010743:Phospholipids; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C099252:oxidized low density lipoprotein; C039351:platelet activating factor receptor; C052518:WEB 2086; D000244:Adenosine Diphosphate; C037913:CV 3988; D003094:Collagen; D013917:Thrombin