Homocysteine exerts cell type-specific inhibition of AP-1 transcription factor

Homocysteine (Hcy) exerts either promoting or suppressive effects on mitogenesis in a cell type-specific manner. Hey elicits proliferation of vascular smooth muscle cells, but is rather inhibitory to growth of endothelial cells and NIH/3T3 cells. In NIH/3T3 cells, we found that physiologically relevant concentrations (20-100 mu M) of Hcy inhibit the activity of activating protein-1 (AP-1) transcription factor, although it is capable of eliciting immediate-early signaling events. Hey induced p44/42 mitogen-activated protein kinase (MAPK) phosphorylation in control cells, but not in dominant negative p21(ras) transfected cells, indicating induction of the Ras-MAPK pathway. Hey also induced the activity of serum response factor and expression of c-fos and c-jun genes. Despite the activation of these upstream events, Hey potently inhibited AP-1 activity. Oxidized forms of Hey (Hcy thiolactone, homocystine) were less effective in affecting AP-1. Hey-mediated inhibition of AP-1 activity was not observed in A7r5 vascular smooth muscle cells. These results demonstrate that Hey exerts cell type- and redox-specific inhibition of AP-1 dependent biological events. (C) 2000 Elsevier Science Inc.