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

Emi Nakano, Fatai A. Taiwo, Desmond Nugent, Helen R. Griffiths, Sarah Aldred, Martha Paisi, Mabel Kwok, Purvi Bhatt, Marilyn H. E. Hill, Stuart Moat, and Hilary J. Powers

Human Nutrition Unit, The university of Sheffield, Sheffield S5 7AU

Corresponding Author: e.nakano{at}sheffield.ac.uk

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

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