Copper-induced apoptosis and immediate early gene expression in macrophages

The death of macrophage-derived foam cells contributes to the formation of the lipid core in atherosclerotic lesions. Although the underlying mechanism is not yet clear, apoptosis has been shown to be responsible, at least in part, for the cell death of lipid-laden macrophages in atherosclerotic plaques. In the present study, we demonstrated that copper, in the presence of 8-hydroxyquinoline, was able to induce apoptosis of murine J774.A1 cells in culture. Ceruloplasmin exerts similar a effect, but not iron or hemin. Further experiments demonstrated that the expression of immediate early genes, including c-jun, c-fos and egr-1, was also induced by copper treatment in these cells, although only egr-1 mRNA was induced in a time- and dose-dependent manner. The antioxidant, N-acetylcysteine, exhibited remarkable inhibitory effect on the copper-induced apoptosis dose-dependently. Time course experiment revealed that prior treatment of cells with N-acetylcysteine is essential for the anti-apoptotic effect of this compound. Results also demonstrated that under the condition; in which N-acetylcysteine inhibited the copper-induced apoptosis, this antioxidant also abolished the gene expression of egr-1. Collectively, these results suggest that egr-1 gene expression is closely associated with the apoptosis induced by copper in macrophages. Copyright (C) 1999 Elsevier Science Ireland Ltd.