title: Myeloperoxidase-derived oxidants modify apolipoprotein A-I and generate dysfunctional high-density lipoproteins: comparison of hypothiocyanous acid (HOSCN) with hypochlorous acid (HOCl).
abstract: Oxidative modification of HDLs (high-density lipoproteins) by MPO (myeloperoxidase) compromises its anti-atherogenic properties, which may contribute to the development of atherosclerosis. Although it has been established that HOCl (hypochlorous acid) produced by MPO targets apoA-I (apolipoprotein A-I), the major apolipoprotein of HDLs, the role of the other major oxidant generated by MPO, HOSCN (hypothiocyanous acid), in the generation of dysfunctional HDLs has not been examined. In the present study, we characterize the structural and functional modifications of lipid-free apoA-I and rHDL (reconstituted discoidal HDL) containing apoA-I complexed with phospholipid, induced by HOSCN and its decomposition product, OCN- (cyanate). Treatment of apoA-I with HOSCN resulted in the oxidation of tryptophan residues, whereas OCN- induced carbamylation of lysine residues to yield homocitrulline. Tryptophan residues were more readily oxidized on apoA-I contained in rHDLs. Exposure of lipid-free apoA-I to HOSCN and OCN- significantly reduced the extent of cholesterol efflux from cholesterol-loaded macrophages when compared with unmodified apoA-I. In contrast, HOSCN did not affect the anti-inflammatory properties of rHDL. The ability of HOSCN to impair apoA-I-mediated cholesterol efflux may contribute to the development of atherosclerosis, particularly in smokers who have high plasma levels of SCN- (thiocyanate).
authors.affiliation: The Heart Research Institute, 7 Eliza St, Newtown, NSW 2042, Australia.
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Hadfield
authors.forename: David I
authors.initials: DI
authors.lastname: Pattison
authors.forename: Bronwyn E
authors.initials: BE
authors.lastname: Brown
authors.forename: Liming
authors.initials: L
authors.lastname: Hou
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davies
authors.forename: Clare L
authors.initials: CL
authors.lastname: Hawkins
mesh_terms: D000595:Amino Acid Sequence; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism*; D013861:Thiocyanates / Q000378:metabolism / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; D019040:E-Selectin; D008075:Lipoproteins, HDL; D016877:Oxidants; D010455:Peptides; D013861:Thiocyanates; D019010:Vascular Cell Adhesion Molecule-1; C517667:hypothiocyanous acid; D018799:Intercellular Adhesion Molecule-1; D006997:Hypochlorous Acid; D002784:Cholesterol; D009195:Peroxidase