© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
All ApoB-Containing Lipoproteins Induce Monocyte Chemotaxis and Adhesion When Minimally Modified
Modulation of Lipoprotein Bioactivity by Platelet-Activating Factor Acetylhydrolase
From the Division of Endocrinology and Metabolism (C.L., F.S., T.S., S.Hörkkö, J.L.W., P.D.R.), Department of Medicine, University of California, San Diego, and the Division of Cardiology (S.Hama, M.N.), Department of Medicine, University of California, Los Angeles, Calif; the Division of Endocrinology (P.V.S.), Rush Medical College, Chicago, Ill; and the Department of Medicine (M.M.), University of Shizuoka, Shizuoka, Japan.
Correspondence to Peter Reaven, MD, Division of Endocrinology and Metabolism, Department of Medicine, 0682, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0682.
Abstract—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
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.
Key Words: atherosclerosis • lipid peroxidation • platelet-activating factor acetylhydrolase • autoantibodies • LDL oxidation
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