title: Effect of 7,8-dihydroneopterin mediated CD36 down regulation and oxidant scavenging on oxidised low-density lipoprotein induced cell death in human macrophages.
abstract: The role of CD36 in oxidised low-density lipoprotein (oxLDL) mediated cell death was examined by down regulating the receptor level with the macrophage generated antioxidant 7,8-dihydroneopterin. Down regulation of CD36 protein levels in human monocyte derived macrophages by 7,8-dihydroneopterin corresponded to a decrease in CD36-mRNA. The oxidation products of 7,8-dihydroneopterin, dihydroxanthopterin and neopterin did not significantly down regulate CD36. The CD36 down regulation resulted in a decrease in oxLDL uptake measured as 7-ketocholesterol accumulation. Though less oxLDL was taken up by the macrophages as a result of the 7,8-dihydroneopterin induced down regulation in CD36 levels, the cytotoxicity of the oxLDL was not decreased. Addition of 7,8-dihydroneopterin to oxLDL treated macrophages decreased the concentration of intracellular oxidants. In the presence of oxLDL, 7,8-dihydroneopterin was oxidised to neopterin showing that the 7,8-dihydroneopterin was scavenging intracellular oxidants generated in response to the oxLDL. The results show CD36 down regulation does not protect human macrophages form oxLDL cytotoxicity but 7,8-dihydroneopterin intracellular oxidant scavenging is protective.
authors.affiliation: Free Radical Biochemistry Laboratory, School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand.
authors.forename: Anastasia A
authors.initials: AA
authors.lastname: Shchepetkina
authors.affiliation: Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Barry D
authors.initials: BD
authors.lastname: Hock
authors.affiliation: Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Allison
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kennedy
authors.affiliation: Free Radical Biochemistry Laboratory, School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand; Department of Radiology, University of Otago, Christchurch, New Zealand. Electronic address: Steven.Gieseg@canterbury.ac.nz.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gieseg
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D018955:CD36 Antigens / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D019798:Neopterin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D016877:Oxidants; C099252:oxidized low density lipoprotein; C000976:7,8-dihydroneopterin; D019798:Neopterin
keywords: 7,8-dihydroneopterin; 7-ketocholesterol; 7KC; CD36; DHE; HMDM; LDL; NADPH-oxidase; NOX; PBS; PPAR-γ; acLDL; acetylated low density lipoprotein; cell-death; dihydroethidium; human monocyte-derived macrophage; low density lipoprotein; macrophage; neopterin; oxLDL; oxidised low density lipoprotein; peroxisome proliferator-activated receptor gamma; phosphate buffered saline; regulation