title: Manganese enhances peroxynitrite and leukotriene E4 formation in bovine aortic endothelial cells exposed to arsenic.
abstract: Long-term exposure to arsenic in drinking water has been linked to cancer and other health effects, including cardiovascular disease. Arsenic in the environment is found in combination with a range of metals that could influence its toxicity. Manganese, in particular, is a metal that is typically found in conjunction with arsenic in contaminated groundwater. Peroxynitrite is a powerful oxidant formed from the reaction between nitric oxide and superoxide anion. Arsenic has been shown to increase the formation of peroxynitrite in bovine aortic endothelial cells (BAECs) and promote the formation of 3-nitrotyrosine (3-NY) in the atherosclerotic plaque of ApoE-/-/LDLr-/- mice. Arsenic exposure also increases leukotriene E4 (LTE4) formation in both the mice and BAECs, an effect that is partially reversed by the addition of Nomega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor. In the present study, we investigated the effect of adding nontoxic concentrations of manganese along with arsenic to BAEC cultures. Manganese increased arsenic toxicity and enhanced peroxynitrite, 3-NY, and LTE4 formation in BAECs. Addition of LNAME reduced 3-NY formation induced by arsenic/manganese mixtures, but in contrast to its effect on arsenic alone, L-NAME actually increased LTE4 synthesis in BAECs treated with the arsenic/manganese combination. Overall, these data suggest that manganese may exacerbate the toxic effects of arsenic on the vascular system.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences and Center for Environmental Health Sciences, The University of Montana, Missoula, 59812, USA.
authors.forename: Melisa
authors.initials: M
authors.lastname: Bunderson
authors.forename: Flavia
authors.initials: F
authors.lastname: Pereira
authors.forename: Mark C
authors.initials: MC
authors.lastname: Schneider
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Shaw
authors.forename: J Douglas
authors.initials: JD
authors.lastname: Coffin
authors.forename: Howard D
authors.initials: HD
authors.lastname: Beall
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001151:Arsenic / Q000633:toxicity*; D018053:Arsenites / Q000633:toxicity; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017999:Leukotriene E4 / Q000378:metabolism*; D008345:Manganese / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism*; D017670:Sodium Compounds / Q000633:toxicity; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D018053:Arsenites; D004338:Drug Combinations; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D017670:Sodium Compounds; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D008345:Manganese; C017947:sodium arsenite; D017999:Leukotriene E4; D001151:Arsenic; D019331:NG-Nitroarginine Methyl Ester