Protective role of glutathione synthesis in response to oxidized low density lipoprotein in human vascular endothelial cells

Impairment of endothelial cells by oxidized low density lipoprotein (OxLDL) is believed to be the first step in atherogenesis. It is also believed tha t oxidative stress/antioxidant imbalance is involved in the cell damage by OxLDL. However, little is known about the interaction between OxLDL and ant ioxidants. In this study, we show that treatment of human vascular endothel ial cells with OxLDL caused a gradual increase of glutathione (gamma-glutam ylcysteinyl glycine, GSH) levels in 24 h. OxLDL increased the intracellular levels of reactive oxygen species (ROS) and stimulated the expression of g amma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme for the GSH synthesis, the mitogen-activated protein kinase (MAPK) activity, an d the AP-1-DNA binding activity. The luciferase activity of gamma-GCS promo ter containing AP-1 site was activated by OxLDL. Collectively, OxLDL induce s gamma-GCS expression mediated by AP-1 resulting in an increase of GSH lev els. The MAPK activity stimulated by ROS may be involved in the activation of AP-1. The increase in GSH by OxLDL may afford cellular protection agains t OxLDL-induced oxidative stress. (C) 1999 Elsevier Science Inc.