© 1999 American Heart Association, Inc.
Molecular Medicine |
Evidence That Phospholipid Oxidation Products and/or Platelet-Activating Factor Play an Important Role in Early Atherogenesis
In Vitro and In Vivo Inhibition by WEB 2086
From the Departments of Medicine/Cardiology (G.S., N.L., P.T.S., J.A.B.), Pathology (J.A.B.), and Psychiatry and Biobehavioral Sciences and the Neuropsychiatric Institute (K.F.F.), University of California, Los Angeles, Calif.
Correspondence to Ganesamoorthy Subbanagounder, PhD, Department of Medicine/Cardiology, Center for the Health Sciences, Room 47-123, UCLA Medical Center, Los Angeles, CA 90095-1679. E-mail gsubbana{at}pathology.medsch.ucla.edu
Abstract—The goal of the
present studies was to determine whether phospholipid oxidation
products and/or platelet-activating factor (PAF) are mediators
of early atherogenesis in vivo. Monocyte–endothelial
cell interactions have been shown to play an important role in early
atherogenesis. We and others have demonstrated that PAF and
phospholipid oxidation products, present in atherosclerotic
lesions, including
1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine
(POVPC),
1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine
(PGPC), and 1-palmitoyl-2-epoxyisoprostane
E2-sn-glycero-3-phosphocholine (PEIPC),
mediate the activation of monocytes and/or endothelial
cells in vitro. Previous studies have shown that the action of PAF and
PAF-like ether-containing phospholipids was inhibited by WEB 2086. We
now demonstrate that pretreatment of human aortic
endothelial cells with WEB 2086 (10 µmol/L) and
several other PAF antagonists before treatment with POVPC
and PEIPC but not PGPC prevented the activation of the
endothelial cells to bind monocytes. We present
evidence to suggest that this inhibition is not mediated by the PAF
receptor. The role of bioactive oxidized phospholipids in fatty streak
formation was tested using C57BL/6J LDL R-/- mice fed a chow or
Western diet for 5 weeks with or without WEB 2086 mixed with drinking
water. Quantitative electrospray ionization mass spectrometry showed
similar concentrations of WEB 2086 in the plasma of mice on both diets
(
4 to 5 µmol/L); this concentration was
inhibitory in vitro. Administration of WEB 2086 did not
affect the lipid composition of mouse plasma. However, fatty streak
formation was reduced by 62% in animals fed a Western diet, whereas no
change was observed in the small lesions of mice on a chow diet. These
studies provide evidence that PAF and/or PAF-like phospholipid
oxidation products are important mediators of atherosclerotic
lesion development in vivo and that specific receptor
antagonists for these molecules may represent a
novel therapeutic modality.
Key Words: atherosclerosis • oxidized phospholipid • platelet-activating factor • WEB 2086 • platelet-activating factor–like lipid
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