All ApoB-containing lipoproteins induce monocyte chemotaxis and adhesion when minimally modified - Modulation of lipoprotein bioactivity by platelet-activating factor acetylhydrolase

Mildly oxidized LDL has many proinflammatory properties, including the stim ulation of monocyte chemotaxis and adhesion, that are important in the deve lopment of atherosclerosis. Although ApoB-containing lipoproteins other tha n LDL may enter the artery wall and undergo oxidation, very little is known regarding their proinflammatory potential. LDL, IDL, VLDL, postprandial re mnant particles, and chylomicrons were mildly oxidized by fibroblasts overe xpressing 15-lipoxygenase (15-LO) and tested for their ability to stimulate monocyte chemotaxis and adhesion to endothelial cells. When conditioned on 15-LO cells, LDL, IDL, but not VLDL increased monocyte chemotaxis and adhe sion approximate to 4-fold. Chylomicrons and postprandial remnant particles were also bioactive. Although chylomicrons had a high 18:1/18:2 ratio, sim ilar to that of VLDL, and should presumably be less susceptible to oxidatio n, they contained (in contrast to VLDL) essentially no platelet-activating factor acetylhydrolase (PAF-AH) activity. Because PAF-AH activity of lipopr oteins may be reduced in vivo by oxidation or glycation, LDL, IDL, and VLDL were treated in vitro to reduce PAF-AH activity and then conditioned on 15 -lipoxygenase cells. All 3 PAF-AH-depleted lipoproteins, including VLDL, ex hibited increased stimulation of monocyte chemotaxis and adhesion. In a sim ilar manner, lipoproteins from Japanese subjects with a deficiency of plasm a PAF-AH activity were also markedly more bioactive, and stimulated monocyt e adhesion nearly 2-fold compared with lipoproteins from Japanese control s ubjects with normal plasma PAF-AH. For each lipoprotein, bioactivity reside d in the lipid fraction and monocyte adhesion could be blocked by PAF-recep tor antagonists. These data suggest that the susceptibility of plasma lipop roteins to develop proinflammatory activity is in part related to their 18: 1/18:2 ratio and PAF-AH activity, and that bioactive phospholipids similar to PAF are generated during oxidation of each lipoprotein. Moreover, LDL, I DL, postprandial remnant particles, and chylomicrons and PAF-AH-depleted VL DL all give rise to proinflammatory lipids when mildly oxidized.