Low levels of arsenic trioxide stimulate proliferative signals in primary vascular cells without activating stress effector pathways

Chronic human exposure to low levels of inorganic arsenic increases the inc idence of vascular diseases and specific cancers. Exposure of endothelial c ells to environmentally relevant concentrations of arsenic trioxide (arseni te) induces oxidant formation, activates the transcription factor NF-kappa B, and increases DNA synthesis (Barchowsky et al., Free Radic. Biol. Med. 2 1, 783-790, 1996). We show, in the current study, that arsenite induces con centration-dependent cell proliferation or death in primary porcine aortic endothelial cells. Low concentrations caused cell proliferation and were as sociated with increased superoxide and H2O2 accumulation, cSrc activity, H2 O2-dependent tyrosine phosphorylation, and NF-kappa B-dependent transcripti on. These concentrations were insufficient to activate MAP kinases. However , the MAP kinases, extracellular signal-regulated kinase and p38, were acti vated in response to levels of arsenite that caused tell death. These data suggest that arsenite-induced oxidant accumulation and subsequent activatio n of tyrosine phosphorylation represent a MAPK-independent pathway for phen otypic change and proliferation in vascular cells. (C) 1999 Academic Press.