Oxidant production, oxLDL uptake, and CD36 levels in human monocyte–derived macrophages are downregulated by the macrophage-generated antioxidant 7,8-dihydroneopterin.
The severity of atheroma burden in patients strongly correlates to increasing levels of plasma neopterin, the oxidation product of 7,8-dihydroneopterin. Interferon-γ stimulation of macrophages causes the synthesis of 7,8-dihydroneopterin, a potent antioxidant that inhibits oxidative damage to cells, and the cytotoxicity of oxidized low-density lipoprotein (oxLDL) to monocyte-like U937 cells but not THP-1 cells. With human monocyte-derived macrophages (HMDMs), oxLDL triggered a large oxidative stress, causing the rapid loss of cellular glutathione, glyceradehyde-3-phosphate dehydrogenase (GAPDH) inhibition, and eventual loss of viability without caspase-3 activation. Inhibition of oxLDL cytotoxicity to HMDMs occurred at 7,8-dihydroneopterin concentrations >100 μM. The oxLDL-mediated glutathione loss and GAPDH inactivation was inhibited by 7,8-dihydroneopterin. 7,8-Dihydroneopterin rapidly entered the HMDMs, suggesting that much of the protective effect was scavenging of intracellular oxidants generated in response to oxLDL. OxLDL uptake by HMDMs was reduced by 30% by 7,8-dihydroneopterin. Immunoblot analysis suggests that this decrease in oxLDL uptake was due to a significant downregulation in the levels of CD36. These results imply that 7,8-dihydroneopterin protects human macrophages both by scavenging oxidants generated in response to oxLDL and by decreasing CD36-mediated uptake of oxLDL.
Gieseg
Steven P
SP
Free Radical Biochemistry Laboratory, School of Biological Sciences, University of Canterbury, Christchurch, New Zealand. steven.gieseg@canterbury.ac.nz
Amit
Zunika
Z
Yang
Ya-Ting
YT
Shchepetkina
Anastasia
A
Katouah
Hanadi
H
D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D018955:CD36 Antigens / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019798:Neopterin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D020298:U937 Cells
D000975:Antioxidants; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D016877:Oxidants; C099252:oxidized low density lipoprotein; C000976:7,8-dihydroneopterin; D019798:Neopterin; D020169:Caspases; D005978:Glutathione