Activation of vascular cells by PAF-like lipids in oxidized LDL

Abstract

The components of inflammation, including macrophages, cytokines and lipid inflammatory mediators, have a role in atherosclerosis. A key lipid mediator in regulated, physiologic inflammation is platelet-activating factor (PAF). PAF activates cells, including monocytes, through a single molecularly characterized receptor, the PAF receptor (PAFR), at exceedingly low concentrations. The PAFR recognizes the short residue, an acetate residue, at the 2-position of the phospholipid, and this sharp specificity precludes receptor activation by other related phosphatidylcholines. Oxidation of low-density lipoproteins (LDLs) is an early and causal step in atherosclerosis that generates inflammatory compounds leading to foam cell formation. One class of oxidatively generated inflammatory compounds are phospholipids that structurally mimic PAF, the PAF-like lipids. Oxidation of LDLs fragments and derivatizes the fatty acid residues at the 2-position of the phosphatidylcholines that comprise the shell of LDLs, an event that allows certain oxidized phospholipids to interact with and activate the PAFR. We know that these products activate polymorphonuclear leukocytes, but because the function of the PAFR differs among cells, we do not know if monocytes or platelets themselves respond to PAF-like lipids. Here, we show that PAF-like lipids from oxidized LDLs are potent and serve as specific agonists for all cells that express the PAFR.