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

E. Nakano, F.A. Taiwo, D. Nugent, Helen R. Griffiths, S. Aldred, M. Paisi, M. Kwok, P. Bhatt, M.H.E Hill, S. Moat, H.J. Powers

Research output: Contribution to journalArticle

Abstract

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. Copyright © 2005 by the American Society for Biochemistry and Molecular Biology, Inc.

Original languageEnglish
Pages (from-to)484-493
Number of pages10
JournalJournal of Lipid Research
Volume46
Issue number3
DOIs
Publication statusPublished - Mar 2005

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Endothelial cells
Homocysteine
LDL Lipoproteins
Endothelial Cells
Methionine
Human Umbilical Vein Endothelial Cells
Folic Acid
Macrophages
Hydroxyl Radical
In Vitro Techniques
Atherosclerosis
Scavenger Receptors
Sulfhydryl Compounds
Oxidants
Metabolism
Cysteine
Glutamic Acid
Up-Regulation
Fluxes

Bibliographical note

Copyright © 2005 by Lipid Research, Inc.

Keywords

  • folate
  • hydroxyl
  • low density lipoprotein
  • macrophage
  • s-adenosyl methionine

Cite this

Nakano, E. ; Taiwo, F.A. ; Nugent, D. ; Griffiths, Helen R. ; Aldred, S. ; Paisi, M. ; Kwok, M. ; Bhatt, P. ; Hill, M.H.E ; Moat, S. ; Powers, H.J. / Downstream effects on human low density lipoprotein of homocysteine exported from endothelial cells in an in vitro system. In: Journal of Lipid Research. 2005 ; Vol. 46, No. 3. pp. 484-493.
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Nakano, E, Taiwo, FA, Nugent, D, Griffiths, HR, Aldred, S, Paisi, M, Kwok, M, Bhatt, P, Hill, MHE, Moat, S & Powers, HJ 2005, 'Downstream effects on human low density lipoprotein of homocysteine exported from endothelial cells in an in vitro system', Journal of Lipid Research, vol. 46, no. 3, pp. 484-493. https://doi.org/10.1194/jlr.M400339-JLR200

Downstream effects on human low density lipoprotein of homocysteine exported from endothelial cells in an in vitro system. / Nakano, E.; Taiwo, F.A.; Nugent, D.; Griffiths, Helen R.; Aldred, S.; Paisi, M.; Kwok, M.; Bhatt, P.; Hill, M.H.E; Moat, S.; Powers, H.J.

In: Journal of Lipid Research, Vol. 46, No. 3, 03.2005, p. 484-493.

Research output: Contribution to journalArticle

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T1 - Downstream effects on human low density lipoprotein of homocysteine exported from endothelial cells in an in vitro system

AU - Nakano, E.

AU - Taiwo, F.A.

AU - Nugent, D.

AU - Griffiths, Helen R.

AU - Aldred, S.

AU - Paisi, M.

AU - Kwok, M.

AU - Bhatt, P.

AU - Hill, M.H.E

AU - Moat, S.

AU - Powers, H.J.

N1 - Copyright © 2005 by Lipid Research, Inc.

PY - 2005/3

Y1 - 2005/3

N2 - 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. Copyright © 2005 by the American Society for Biochemistry and Molecular Biology, Inc.

AB - 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. Copyright © 2005 by the American Society for Biochemistry and Molecular Biology, Inc.

KW - folate

KW - hydroxyl

KW - low density lipoprotein

KW - macrophage

KW - s-adenosyl methionine

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