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 stimulation of monocyte chemotaxis and adhesion, that are important in the development of atherosclerosis. Although ApoB-containing lipoproteins other than LDL may enter the artery wall and undergo oxidation, very little is known regarding their proinflammatory potential. LDL, IDL, VLDL, postprandial remnant particles, and chylomicrons were mildly oxidized by fibroblasts overexpressing 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 adhesion approximately 4-fold. Chylomicrons and postprandial remnant particles were also bioactive. Although chylomicrons had a high 18:1/18:2 ratio, similar to that of VLDL, and should presumably be less susceptible to oxidation, they contained (in contrast to VLDL) essentially no platelet-activating factor acetylhydrolase (PAF-AH) activity. Because PAF-AH activity of lipoproteins 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, exhibited increased stimulation of monocyte chemotaxis and adhesion. In a similar manner, lipoproteins from Japanese subjects with a deficiency of plasma PAF-AH activity were also markedly more bioactive, and stimulated monocyte adhesion nearly 2-fold compared with lipoproteins from Japanese control subjects with normal plasma PAF-AH. For each lipoprotein, bioactivity resided in the lipid fraction and monocyte adhesion could be blocked by PAF-receptor antagonists. These data suggest that the susceptibility of plasma lipoproteins 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, IDL, postprandial remnant particles, and chylomicrons and PAF-AH-depleted VLDL all give rise to proinflammatory lipids when mildly oxidized.
Lee
C
C
Division of Endocrinology, Department of Medicine, University of California, San Diego, USA.
Sigari
F
F
Segrado
T
T
Hörkkö
S
S
Hama
S
S
Subbaiah
P V
PV
Miwa
M
M
Navab
M
M
Witztum
J L
JL
Reaven
P D
PD
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D001055:Apolipoproteins B / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000502:physiology; D001161:Arteriosclerosis / Q000209:etiology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D002914:Chylomicrons / Q000378:metabolism; D003300:Copper / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism; D008074:Lipoproteins / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010084:Oxidation-Reduction; D010741:Phospholipases A / Q000502:physiology*
D001055:Apolipoproteins B; D002914:Chylomicrons; D008074:Lipoproteins; D003300:Copper; D001093:Arachidonate 15-Lipoxygenase; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase