Arsenite inhibits Ras-dependent activation of ERK but activates ERK in thepresence of oncogenic Ras in baboon vascular smooth muscle cells

Exposure to arsenical compounds enhances the risk of atherosclerosis. The r eason is unknown but it might be because an effect of arsenite (As3+) on pl aque smooth muscle cells (SMCs) activation of extracellular signal-regulate d kinase (ERK), a crucial mediator of SMC function. We found that arsenite inhibits the activation of ERK by platelet-derived growth factor-BB (PDGF-B B). This inhibitory effect depends on the time of arsenite exposure, is rev ersible, and is attenuated by preincubation of SMCs with the antioxidant N- acetyl-cysteine. These observations are consistent with the assumption that oxidative stress is involved. The blockade of ERK by arsenite may be media ted by an inhibition of Ras as arsenite prevents GTP-loading of Ras in resp onse to PDGF-BB. Moreover, the Ras blockade by arsenite is not specific for PDGF-BB because it was also observed following stimulation of SMCs with EG F. To address the role of Ras, we expressed constitutively active, GTP-boun d Ha-Ras (V12Ras). Unexpectedly, in V12Ras expressing-SMCs, arsenite stimul ates ERK, but still decreases ERK activity in the presence of PDGF-BB. Our data suggest that arsenite inhibits the Ras/ERK pathway in SMCs, and that a rsenite may activate ERK in Ras-transformed cells by mechanisms different f rom those employed by growth factors.