Journal
MOLECULAR AND CELLULAR BIOCHEMISTRY
Volume 217, Issue 1-2, Pages 131-136Publisher
KLUWER ACADEMIC PUBL
DOI: 10.1023/A:1007276812824
Keywords
Ras inhibition by arsenite; smooth muscle; signal transduction; oxidative stress; V12-Ras; PDGF-BB; EGF
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL030946, P01HL018645] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL30946, HL18645] Funding Source: Medline
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Exposure to arsenical compounds enhances the risk of atherosclerosis. The reason is unknown but it might be because an effect of arsenite (As3+) on plaque smooth muscle cells (SMCs) activation of extracellular signal-regulated kinase (ERK), a crucial mediator of SMC function. We found that arsenite inhibits the activation of ERK by platelet-derived growth factor-BB (PDGF-BB). This inhibitory effect depends on the time of arsenite exposure, is reversible, 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 mediated by an inhibition of Ras as arsenite prevents GTP-loading of Ras in response 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 EGF. To address the role of Ras, we expressed constitutively active, GTP-bound Ha-Ras (V12Ras). Unexpectedly, in V12Ras expressing-SMCs, arsenite stimulates 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 arsenite may activate ERK in Ras-transformed cells by mechanisms different from those employed by growth factors.
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