title: Comparative reactivity of the myeloperoxidase-derived oxidants HOCl and HOSCN with low-density lipoprotein (LDL): Implications for foam cell formation in atherosclerosis.
abstract: Atherosclerosis is characterised by the accumulation of lipids within macrophages in the artery wall. Low-density lipoprotein (LDL) is the source of this lipid, owing to the uptake of oxidised LDL by scavenger receptors. Myeloperoxidase (MPO) released by leukocytes during inflammation produces oxidants that are implicated in atherosclerosis. Modification of LDL by the MPO oxidant hypochlorous acid (HOCl), results in extensive lipid accumulation by macrophages. However, the reactivity of the other major MPO oxidant, hypothiocyanous acid (HOSCN) with LDL is poorly characterised, which is significant given that thiocyanate is the favoured substrate for MPO. In this study, we comprehensively compare the reactivity of HOCl and HOSCN with LDL, and show key differences in the profile of oxidative damage observed. HOSCN selectively modifies Cys residues on apolipoprotein B100, and oxidises cholesteryl esters resulting in formation of lipid hydroperoxides, 9-hydroxy-10,12-octadecadienoic acid (9-HODE) and F2-isoprostanes. The modification of LDL by HOSCN results macrophage lipid accumulation, though generally to a lesser extent than HOCl-modified LDL. This suggests that a change in the ratio of HOSCN:HOCl formation by MPO from variations in plasma thiocyanate levels, will influence the nature of LDL oxidation in vivo, and has implications for the progression of atherosclerosis.
authors: The Heart Research Institute, 7 Eliza St, Newtown, NSW 2042, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
authors: Fahd O
authors: FO
authors: Ismael
authors: School of Medicine and Pharmacology, University of Western Australia, Level 4 Medical Research Foundation Building, 50 Murray St, Perth, WA 6000, Australia.
authors: Julie M
authors: JM
authors: Proudfoot
authors: The Heart Research Institute, 7 Eliza St, Newtown, NSW 2042, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
authors: Bronwyn E
authors: BE
authors: Brown
authors: Faculty of Science, University of Technology Sydney, Broadway, NSW 2007, Australia.
authors: David M
authors: DM
authors: van Reyk
authors: School of Medicine and Pharmacology, University of Western Australia, Level 4 Medical Research Foundation Building, 50 Murray St, Perth, WA 6000, Australia.
authors: Kevin D
authors: KD
authors: Croft
authors: The Heart Research Institute, 7 Eliza St, Newtown, NSW 2042, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Dept. of Biomedical Sciences, Panum Institute, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
authors: Michael J
authors: MJ
authors: Davies
authors: The Heart Research Institute, 7 Eliza St, Newtown, NSW 2042, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: hawkinsc@hri.org.au.
authors: Clare L
authors: CL
authors: Hawkins
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000737:chemistry; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis; D002788:Cholesterol Esters / Q000096:biosynthesis; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006997:Hypochlorous Acid / Q000737:chemistry / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016877:Oxidants / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism*; D013861:Thiocyanates / Q000737:chemistry / Q000378:metabolism*
chemical_list: D053299:Apolipoprotein B-100; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D016877:Oxidants; D013861:Thiocyanates; C517667:hypothiocyanous acid; D006997:Hypochlorous Acid; D002784:Cholesterol; D009195:Peroxidase
keywords: Atherosclerosis; Cholesterol; Low-density lipoprotein; Myeloperoxidase; Oxidation; Thiocyanate