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Originally published In Press as doi:10.1194/jlr.M400339-JLR200 on December 1, 2004

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Journal of Lipid Research, Vol. 46, 484-493, March 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Downstream effects on human low density lipoprotein of homocysteine exported from endothelial cells in an in vitro system

E. Nakano*, F. A. Taiwo{dagger}, D. Nugent{dagger}, H. R. Griffiths§, S. Aldred§, M. Paisi*, M. Kwok*, P. Bhatt*, M. H. E. Hill*, S. Moat** and H. J. Powers1,*

* Human Nutrition Unit, University of Sheffield, Coleridge House, The Northern General Hospital, Sheffield S5 7AU, United Kingdom
{dagger} Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, United Kingdom
§ Department of Life and Health Sciences, Aston University, Birmingham B4 7ET, United Kingdom
** Department of Medical Biochemistry and Immunology, University Hospital of Wales, Cardiff CF14 4XW, United Kingdom

1 To whom correspondence should be addressed. e-mail: h.j.powers{at}sheffield.ac.uk

A model system is presented using human umbilical vein endothelial cells (HUVECs) to investigate the role of homocysteine (Hcy) in atherosclerosis. HUVECs are shown to export Hcy at a rate determined by the flux through the methionine/Hcy pathway. Additional methionine increases intracellular methionine, decreases intracellular folate, and increases Hcy export, whereas additional folate inhibits export. An inverse relationship exists between intracellular folate and Hcy export. Hcy export may be regulated by intracellular S-adenosyl methionine rather than by Hcy. Human LDLs exposed to HUVECs exporting Hcy undergo time-related lipid oxidation, a process inhibited by the thiol trap dithionitrobenzoate. This is likely to be related to the generation of hydroxyl radicals, which we show are associated with Hcy export. Although Hcy is the major oxidant, cysteine also contributes, as shown by the effect of glutamate. Finally, the LDL oxidized in this system showed a time-dependent increase in uptake by human macrophages, implying an upregulation of the scavenger receptor.

These results suggest that continuous export of Hcy from endothelial cells contributes to the generation of extracellular hydroxyl radicals, with associated oxidative modification of LDL and incorporation into macrophages, a key step in atherosclerosis. Factors that regulate intracellular Hcy metabolism modulate these effects.

Abbreviations: DiI, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; DMPO, 5,5-dimethyl-1-pyrroline N-oxide; EPR, electron paramagnetic resonance; Hcy, homocysteine; HUVEC, human umbilical vein endothelial cell; SAM, S-adenosyl methionine; TBARS, thiobarbituric acid reactive substances; tHcy, total homocysteine

Supplementary key words low density lipoprotein • S-adenosyl methionine • macrophage • hydroxyl • folate




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