title: Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3.
abstract: Treatment of human artery wall cells with apolipoprotein A-I (apoA-I), but not apoA-II, with an apoA-I peptide mimetic, or with high density lipoprotein (HDL), or paraoxonase, rendered the cells unable to oxidize low density lipoprotein (LDL). Human aortic wall cells were found to contain 12-lipoxygenase (12-LO) protein. Transfection of the cells with antisense to 12-LO (but not sense) eliminated the 12-LO protein and prevented LDL-induced monocyte chemotactic activity. Addition of 13(S)-hydroperoxyoctadecadienoic acid [13(S)-HPODE] and 15(S)-hydroperoxyeicosatetraenoic acid [15(S)-HPETE] dramatically enhanced the nonenzymatic oxidation of both 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) and cholesteryl linoleate. On a molar basis 13(S)-HPODE and 15(S)-HPETE were approximately two orders of magnitude greater in potency than hydrogen peroxide in causing the formation of biologically active oxidized phospholipids (m/z 594, 610, and 828) from PAPC. Purified paraoxonase inhibited the biologic activity of these oxidized phospholipids. HDL from 10 of 10 normolipidemic patients with coronary artery disease, who were neither diabetic nor receiving hypolipidemic medications, failed to inhibit LDL oxidation by artery wall cells and failed to inhibit the biologic activity of oxidized PAPC, whereas HDL from 10 of 10 age- and sex-matched control subjects did. We conclude that a) mildly oxidized LDL is formed in three steps, one of which involves 12-LO and each of which can be inhibited by normal HDL, and b) HDL from at least some coronary artery disease patients with normal blood lipid levels is defective both in its ability to prevent LDL oxidation by artery wall cells and in its ability to inhibit the biologic activity of oxidized PAPC.
authors.affiliation: Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: M
authors.initials: M
authors.lastname: Navab
authors.forename: S Y
authors.initials: SY
authors.lastname: Hama
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
authors.forename: K
authors.initials: K
authors.lastname: Hassan
authors.forename: G P
authors.initials: GP
authors.lastname: Hough
authors.forename: A D
authors.initials: AD
authors.lastname: Watson
authors.forename: S T
authors.initials: ST
authors.lastname: Reddy
authors.forename: A
authors.initials: A
authors.lastname: Sevanian
authors.forename: G C
authors.initials: GC
authors.lastname: Fonarow
authors.forename: A M
authors.initials: AM
authors.lastname: Fogelman
mesh_terms: D001011:Aorta / Q000201:enzymology*; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D001161:Arteriosclerosis / Q000097:blood*; D043303:Aryldialkylphosphatase; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D003327:Coronary Disease / Q000097:blood*; D004730:Endothelium, Vascular / Q000201:enzymology*; D004950:Esterases / Q000378:metabolism; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide; D015289:Leukotrienes / Q000737:chemistry; D008041:Linoleic Acids / Q000737:chemistry; D008054:Lipid Peroxides / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008955:Models, Cardiovascular; D009000:Monocytes / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D012016:Reference Values
chemical_list: D015289:Leukotrienes; D008041:Linoleic Acids; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; D020319:Oligodeoxyribonucleotides, Antisense; D010743:Phospholipids; C099252:oxidized low density lipoprotein; C038649:13-hydroperoxy-9,11-octadecadienoic acid; C025086:15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; D006861:Hydrogen Peroxide; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D004950:Esterases; D043303:Aryldialkylphosphatase