Copper and cell-oxidized low-density lipoprotein induces activator protein 1 in fibroblasts, endothelial and smooth muscle cells.

The effect of cupric ion- or endothelial cell-oxidized low-density lipoproteins (LDL) on transcription factor AP1 activation was investigated by electrophoretic mobility shift assay. Both oxidized LDL induced AP1 activation in fibroblasts, endothelial and smooth muscle cells. This phenomenon was also observed in the presence of cycloheximide. alpha-Tocopherol, a lipophilic free radical scavenger, and N-acetylcysteine, an hydrophilic antioxidant, partially inhibited the stimulatory effect of Cu2+-oxidized LDL. LDL modified by the mixture of the oxygen radicals OH. and O2.-, which generated lipid peroxidation products, also initiated AP1 activation, whereas LDL modified by OH. alone, which did not lead to marked LDL lipid peroxidation, was ineffective. Thus, lipid peroxidation products seem at least partially involved in the activation mechanism. Since AP1 activity is essential for the regulation of genes involved in cell growth and differentiation, our study suggests that the oxidative stress induced by oxidized LDL might be related to the fibroproliferative response observed in the atherosclerotic plaque.