Oxidant Production, oxLDL uptake and CD36 levels in Human Monocyte Derived Macrophages are down regulated by the macrophage - generated antioxidant 7,8-dihydroneopterin

Gieseg, S.P and Zunika, Amit and Ya, T.Y and Shchepetkina, A. and Katouah, H. (2010) Oxidant Production, oxLDL uptake and CD36 levels in Human Monocyte Derived Macrophages are down regulated by the macrophage - generated antioxidant 7,8-dihydroneopterin. Antioxidants & Redox Signaling, 13 (10). pp. 1525-1534. ISSN 1557-7716

PDF Oxidant Production...pdf Download (141kB)

Abstract

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. Antioxid. Redox Signal. 13, 1525–1534.

Actions (For repository members only: login required)

View Item