title: Myeloperoxidase-derived reactive chlorinating species from human monocytes target plasmalogens in low density lipoprotein.
abstract: A role for myeloperoxidase (MPO) in atherosclerosis has received considerable attention recently. To identify potential chlorinated lipid products in human low density lipoprotein (LDL), studies were designed to demonstrate that MPO-derived reactive chlorinating species (RCS) target the plasmalogen pool of LDL isolated from peripheral human blood in vitro. The vinyl ether bond of LDL plasmalogens was targeted by MPO-derived RCS, resulting in the release of the 16- and 18-carbon-containing alpha-chloro fatty aldehydes, 2-chlorohexadecanal and 2-chlorooctadecanal, respectively, from the plasmalogen glycerol backbone. Targeting of the LDL plasmalogen vinyl ether bond was dependent on the presence of MPO-derived RCS. Electrospray ionization mass spectrometric analysis of MPO-treated LDL demonstrated that a novel population of unsaturated lysophosphatidylcholine molecular species was produced by a phospholipase A2-independent mechanism. Unsaturated lysophosphatidylcholine molecular species elicited cyclic AMP response element binding protein phosphorylation in RAW 264.7 cells. Additionally, MPO-mediated targeting of both monocyte and LDL plasmalogen pools was demonstrated in phorbol myristate acetate-stimulated human monocytes, resulting in the production of both 2-chlorohexadecanal and 2-chlorooctadecanal. In contrast, alpha-chloro fatty aldehydes were not produced in phorbol myristate acetate-stimulated mouse monocytes. Collectively, the present studies demonstrate a novel MPO-specific mechanism that mediates the production of a novel group of unsaturated lysophosphatidylcholine molecular species and chlorinated aldehydes from both LDL and monocyte plasmalogen pools that may have important effects during inflammatory reactions mediated by monocytes, most notably atherosclerosis.
authors.affiliation: Department of Biochemistry and Molecular Biology, St. Louis University Health Sciences Center, St. Louis, Missouri 63104, USA.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Thukkani
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Albert
authors.forename: Kristin R
authors.initials: KR
authors.lastname: Wildsmith
authors.forename: Maria C
authors.initials: MC
authors.lastname: Messner
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Martinson
authors.forename: Fong-Fu
authors.initials: FF
authors.lastname: Hsu
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D002713:Chlorine / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005990:Glycerol / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism*; D009195:Peroxidase / Q000737:chemistry*; D010741:Phospholipases A / Q000737:chemistry; D054467:Phospholipases A2; D010766:Phosphorylation; D010955:Plasmalogens / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013997:Time Factors
chemical_list: C432398:2-chlorohexadecanal; D000447:Aldehydes; D017362:Cyclic AMP Response Element-Binding Protein; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D010955:Plasmalogens; D002713:Chlorine; D000242:Cyclic AMP; D009195:Peroxidase; D010741:Phospholipases A; D054467:Phospholipases A2; D005990:Glycerol