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-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.

• Authors: Sarah K Baird, Linzi Reid, Mark B Hampton, Steven P Gieseg
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1745 Issue 3 Pg. 361-9 (Sep 30 2005) ISSN: 0006-3002 [Print] Netherlands
• PMID: 16084608 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipoproteins, LDL
• Phosphatidylserines
• Sulfhydryl Compounds
• oxidized low density lipoprotein
• 7,8-dihydroneopterin
• Neopterin
• Interferon-gamma
• CASP3 protein, human
• Caspase 3
• Caspases
• Glutathione

Topics

• Analysis of Variance
• Apoptosis (drug effects)
• Atherosclerosis (metabolism)
• Caspase 3
• Caspases (metabolism)
• Cell Membrane (metabolism)
• Chromatography, High Pressure Liquid
• Fluorescence
• Glutathione (metabolism)
• Humans
• Interferon-gamma (metabolism)
• Lipoproteins, LDL (antagonists & inhibitors)
• Macrophages (metabolism)
• Neopterin (analogs & derivatives, pharmacology)
• Phosphatidylserines (metabolism)
• Sulfhydryl Compounds (metabolism)
• U937 Cells