title: Oxidised low density lipoprotein causes human macrophage cell death through oxidant generation and inhibition of key catabolic enzymes.
abstract: Oxidised low density lipoprotein (oxLDL) is thought to be a significant contributor to the death of macrophage cells observed in advanced atherosclerotic plaques. Using human-derived U937 cells we have examined the effect of cytotoxic oxLDL on oxidative stress and cellular catabolism. Within 3h of the addition of oxLDL, there was a rapid, concentration dependent rise in cellular reactive oxygen species followed by the loss of cellular GSH, and the enzyme activity of both glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and aconitase. The loss of these catabolic enzymes was accompanied by the loss of cellular ATP and lower lactate generation. Addition of the macrophage antioxidant 7,8-dihydroneopterin inhibited the ROS generation, glutathione loss and catabolic inactivation. NOX was shown to be activated by oxLDL addition while apocynin inhibited the loss of GSH and cell viability. The data suggests that oxLDL triggers an excess of ROS production through NOX activation, and catabolic failure through thiol oxidation resulting in cell death.
authors.affiliation: Free Radical Biochemistry Laboratory, School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand; Chemistry Department, Faculty of Applied Science, Umm Al Qura University, Saudi Arabia.
authors.forename: Hanadi
authors.initials: H
authors.lastname: Katouah
authors.affiliation: Free Radical Biochemistry Laboratory, School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand.
authors.forename: Alpha
authors.initials: A
authors.lastname: Chen
authors.affiliation: Free Radical Biochemistry Laboratory, School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand; Faculty of Pharmacy, University Teknologi, MARA, Pulau Pinang, Malaysia.
authors.forename: Izani
authors.initials: I
authors.lastname: Othman
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, Christchurch, New Zealand. Electronic address: Steven.Gieseg@canterbury.ac.nz.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gieseg
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism; D019798:Neopterin / Q000031:analogs & derivatives / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; C000976:7,8-dihydroneopterin; D019344:Lactic Acid; D019798:Neopterin; D000255:Adenosine Triphosphate; C056165:acetovanillone; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D000154:Aconitate Hydratase; D005978:Glutathione
keywords: NADPH-oxidase; NOX; Necrosis: Macrophage; Neopterin; Oxidised low-density lipoprotein