title: Macrophage mediated protein hydroperoxide formation and lipid oxidation in low density lipoprotein are inhibited by the inflammation marker 7,8-dihydroneopterin.
abstract: The formation of oxidised low density lipoprotein (LDL) within the atherosclerotic plaque appears to be a factor in the development of advanced atherosclerotic plaques. LDL oxidation is dependent on the balance of oxidants and antioxidants within the intima. In addition to producing various oxidants, human macrophages release 7,8-dihydroneopterin which in vivo is oxidised to the inflammation marker neopterin. Using macrophage-like THP-1 cells and human monocyte-derived macrophages, we demonstrate that 7,8-dihydroneopterin is a potent inhibitor of cell-mediated LDL oxidation. 7,8-Dihydroneopterin scavenges the chain propagating lipid peroxyl radical, inhibiting both lipid and protein hydroperoxide formation. A significant amount of the hydroperoxide formed during cell-mediated LDL oxidation was protein hydroperoxide. 7,8-Dihydroneopterin oxidation to 7,8-dihydroxanthopterin was only observed in the presence of both cells and LDL, showing that 7,8-dihydroneopterin had no effect on initiating oxidant generation by the cells. 7,8-Dihydroneopterin did not regenerate alpha-tocopherol but competed with it for the lipid peroxyl radical. Although stimulation of both cell types with gamma-interferon failed to produce sufficient 7,8-dihydroneopterin to inhibit LDL oxidation in tissue culture, analysis of advanced atherosclerotic plaque removed from patients showed that total neopterin levels could reach low micromolar concentrations. This suggests that 7,8-dihydroneopterin synthesis by macrophages could play a significant role in the development of atherosclerotic plaques.
authors.affiliation: Free Radical Biochemistry Laboratory, School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Firth
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Crone
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Flavall
authors.forename: Justin A
authors.initials: JA
authors.lastname: Roake
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gieseg
mesh_terms: D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D006432:Hemochromatosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007249:Inflammation; D007371:Interferon-gamma / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry*; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019798:Neopterin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism
chemical_list: D008055:Lipids; D008077:Lipoproteins, LDL; D010545:Peroxides; C099252:oxidized low density lipoprotein; C000976:7,8-dihydroneopterin; C049375:perhydroxyl radical; D019798:Neopterin; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D010100:Oxygen