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 incidence of vascular diseases and specific cancers. Exposure of endothelial cells to environmentally relevant concentrations of arsenic trioxide (arsenite) induces oxidant formation, activates the transcription factor NF-kappaB, and increases DNA synthesis (Barchowsky et al., Free Radic. Biol. Med. 21, 783-790, 1996). We show, in the current study, that arsenite induces concentration-dependent cell proliferation or death in primary porcine aortic endothelial cells. Low concentrations caused cell proliferation and were associated with increased superoxide and H(2)O(2) accumulation, cSrc activity, H(2)O(2)-dependent tyrosine phosphorylation, and NF-kappaB-dependent transcription. These concentrations were insufficient to activate MAP kinases. However, the MAP kinases, extracellular signal-regulated kinase and p38, were activated in response to levels of arsenite that caused cell death. These data suggest that arsenite-induced oxidant accumulation and subsequent activation of tyrosine phosphorylation represent a MAPK-independent pathway for phenotypic change and proliferation in vascular cells.
Barchowsky
A
A
Department of Pharmacology and Toxicology, Dartmouth College and Medical School, Hanover, New Hampshire, 03755, USA.
Roussel
R R
RR
Klei
L R
LR
James
P E
PE
Ganju
N
N
Smith
K R
KR
Dudek
E J
EJ
D000818:Animals; D000906:Antibodies / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001011:Aorta / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D015151:Immunoblotting; D018384:Oxidative Stress / Q000187:drug effects*; D010087:Oxides / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011994:Recombinant Proteins; D019097:Spin Trapping; D013552:Swine; D014162:Transfection / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism
D000906:Antibodies; D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D011994:Recombinant Proteins; D014443:Tyrosine; D006861:Hydrogen Peroxide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D000077237:Arsenic Trioxide