OxLDL induced cell death is inhibited by the macrophage synthesised pterin, 7,8-dihydroneopterin, in U937 cells but not THP-1 cells.
The atherosclerotic plaque is an inflammatory site where macrophage cells are exposed to cytotoxic oxidised low density lipoprotein (oxLDL). Interferon-gamma released from T-cells results in macrophage synthesis of 7,8-dihydroneopterin which has antioxidant and cytoprotective activity. Using the human derived monocyte-like U937 and THP-1 cell lines, we examined whether 7,8-dihydroneopterin could inhibit the cytotoxic effect of oxLDL. In U937 cells, oxLDL caused a dramatic loss of cellular glutathione and caspase independent cell death associated with phosphatidylserine exposure on the plasma membrane. 7,8-Dihydroneopterin completely blocked the cytotoxic effect of oxLDL. In contrast, oxLDL initiated THP-1 cell apoptosis with reduction in cellular thiols, caspase-3 activation and plasma membrane phosphatidylserine exposure. 7,8-Dihydroneopterin was unable to alter these processes or restore the THP-1 cellular thiol content. 7,8-Dihydroneopterin did provide some protection to both THP-1 cells and U937 cells from AAPH derived peroxyl radicals. The preincubation of oxLDL with 7,8-dihydroneopterin did not reduce cytotoxicity, suggesting that 7,8-dihydroneopterin may be acting in U937 cells by scavenging intracellular oxidants generated by the oxLDL. The data show that muM levels of 7,8-dihydroneopterin may prevent oxLDL mediated cellular death within atherosclerotic plaques.
Baird
Sarah K
SK
Free Radical Biochemistry Laboratory, School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand.
Reid
Linzi
L
Hampton
Mark B
MB
Gieseg
Steven P
SP
D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D050197:Atherosclerosis / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005453:Fluorescence; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000378:metabolism*; D019798:Neopterin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D020298:U937 Cells
D008077:Lipoproteins, LDL; D010718:Phosphatidylserines; D013438:Sulfhydryl Compounds; C099252:oxidized low density lipoprotein; C000976:7,8-dihydroneopterin; D019798:Neopterin; D007371:Interferon-gamma; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione