OxLDL induced cell death is inhibited by the macrophage synthesised pterin, 7,8-dihydroneopterin, in U937 cells but not THP-1 cells

Abstract

The atherosclerotic plaque is an inflammatory site where macrophage cells are exposed to cytotoxic oxidised low density lipoprotein (oxLDL). Interferon-γ 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 μM levels of 7,8-dihydroneopterin may prevent oxLDL mediated cellular death within atherosclerotic plaques.