© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Determinants of Bioactivity of Oxidized Phospholipids
Specific Oxidized Fatty Acyl Groups at the sn-2 Position
From the Departments of Medicine (G.S., N.L., J.W.W., H.L., C.R., A.D.W., A.M.F., J.A.B.) and Pathology (J.A.B.) and the Pasarow Mass Spectrometry Laboratory (K.F.F.) and Department of Psychiatry and Biobehavioral Sciences and Neuropsychiatric Institute, University of California, Los Angeles, and the Department of Pathology (D.C.S.), Wake Forest University School of Medicine, Winston-Salem, NC. Norbert Leitinger is currently at the Department of Vascular Biology and Thrombosis Research, University of Vienna, Vienna, Austria.
Correspondence to Ganesamoorthy Subbanagounder, PhD, Department of Medicine/Cardiology, 47-123, Center for the Health Sciences, UCLA Medical Center, Los Angeles, CA 90095-1679. E-mail gsubbanagounder{at}mednet.ucla.edu
Abstract—We previously described 3 bioactive oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC) containing oxovaleroyl (POVPC), glutaroyl (PGPC), and epoxyisoprostane (PEIPC) groups at the sn-2 position that were increased in minimally modified/oxidized low density lipoprotein (MM-LDL) and rabbit atherosclerotic lesions. We demonstrated specific and contrasting effects of POVPC and PGPC on leukocyte-endothelial interactions and described an effect of PEIPC on monocyte binding. The major purpose of the present study was to determine the effects of structural changes on the bioactivities of these 3 lipids. We demonstrate herein that the group at the sn-2 position determines the specific bioactivity and that the substitution of stearoyl for palmitoyl at the sn-1 position or ethanolamine for choline at the sn-3 position of the phospholipid did not alter bioactivity. Oxidized PAPC, oxidized 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine, and oxidized 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphorylethanolamine stimulated monocyte binding and inhibited lipopolysaccharide-induced expression of the neutrophil-binding molecule E-selectin. Furthermore, all oxovaleroyl phospholipids but not the glutaroyl phospholipids induced monocyte binding without an increase in vascular cell adhesion molecule-1 (VCAM-1) expression and inhibited lipopolysaccharide-induced E-selectin expression. In contrast, glutaroyl phospholipids but not oxovaleroyl phospholipids stimulated E-selectin and VCAM-1 expression. We further demonstrate that all parts of the phospholipid molecules are required for these bioactivities. Hydrolysis with phospholipase (PL) A1, PLA2, and PLC strongly reduced the bioactivities of POVPC, PGPC, and mixed isomers of PEIPC. PLD had a smaller but still significant effect. The effects of POVPC and PEIPC could be abolished by sodium borohydride treatment, indicating the importance of the reducible groups (carbonyl and epoxide) in these molecules. In summary, these studies identify 6 new bioactive, oxidized phospholipids that are increased in MM-LDL and, where measured, in atherosclerotic lesions. They thus suggest that a family of phospholipid oxidation products containing oxovaleroyl, glutaroyl, and epoxyisoprostane at the sn-2 position play an important role in the regulation of leukocyte-endothelial interactions, bioactivity being in part controlled by several types of phospholipid hydrolases.
Key Words: atherosclerosis • oxidized phospholipids • monocyte-endothelial interactions • E-selectin • phospholipases
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