Arsenic induces oxidant stress and NF-kappa B activation in cultured aortic endothelial cells.
Chronic exposure to low levels of environmentally derived arsenite are associated with vascular diseases, such as arteriosclerosis. However, the cellular and molecular mechanisms for vascular disease in response to arsenic are not known. These studies investigated the hypothesis that nonlethal levels of arsenic increase intracellular oxidant levels, promote nuclear translocation of trans-acting factors, and are mitogenic. Incubation of second passage vascular endothelial cells with less than 5 microM arsenite for 4 h increased incorporation of [3H]thymidine into genomic DNA, while higher concentrations failed to stimulate or inhibit DNA synthesis. Within 1 h following addition of noncytotoxic concentrations of arsenite, oxidants accumulated and thiol status increased. During this time period, there was increased nuclear retention of NF-kappa B binding proteins and nuclear translocation of NF-kappa B also occurred in response to 100 microM H2O2. Supershift analysis demonstrated that p65/p50 heterodimers accounted for the majority of proteins binding consensus kappa B sequences in cells treated with arsenite or oxidants. The antioxidants, N-acetylcysteine or dimethylfumaric acid, increased intracellular thiol status and prevented both oxidant formation and translocation of NF-kappa B binding proteins in response to arsenite. These data suggest that arsenite initiates vascular dysfunction by activating oxidant-sensitive endothelial cell signaling.
Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA.
A
A
Barchowsky
E J
EJ
Dudek
M D
MD
Treadwell
K E
KE
Wetterhahn
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta; D018053:Arsenites / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007700:Kinetics; D016328:NF-kappa B / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism*; D018384:Oxidative Stress; D017670:Sodium Compounds / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013552:Swine
D000975:Antioxidants; D018053:Arsenites; D016328:NF-kappa B; D016877:Oxidants; D017670:Sodium Compounds; D013438:Sulfhydryl Compounds; C017947:sodium arsenite; D004247:DNA; D006861:Hydrogen Peroxide; D005978:Glutathione