title: Arsenic modulates heme oxygenase-1, interleukin-6, and vascular endothelial growth factor expression in endothelial cells: roles of ROS, NF-κB, and MAPK pathways.
abstract: Chronic arsenic exposure has been linked to an increased risk of vascular diseases. To clarify the molecular mechanisms through which arsenic causes injuries to blood vessels, we analyzed the effects of arsenic trioxide on the cytotoxicity, intracellular reactive oxygen species (ROS), the expression of related genes, and signaling pathways involved in the SVEC4-10 mouse endothelial cells. Arsenic dose-dependently caused SVEC4-10 cell death, which is completely inhibited by α-lipoic acid (LA), a thioreductant, but partially ameliorated by Tiron, a potent superoxide scavenger. The mRNA levels of heme oxygenase-1 (HO-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) were significantly increased by arsenic. The up-regulation of these can be blocked by LA instead of Tiron, suggesting ROS is not important in their increase. HO-1 competitive inhibitor zinc protoporphyrin improved the cytotoxicity of arsenic in an inverted-U dose-response curve, indicating the biphasic hormetic effect of HO-1. HO-1 siRNA decreased VEGF expression in response to arsenic. Arsenic exposure also enhanced NF-E2-related factor 2 (Nrf2) expression and increased activation of nuclear factor-κB (NF-κB). NF-κB inhibitor Bay 11-7082 reduced arsenic-mediated expression of HO-1 and IL-6. Selective blocking of the MAPK pathways with p38 inhibitor SB203580 significantly decreased arsenic-induced HO-1 and VEGF expression, while JNKs inhibitor SP600125 increased IL-6 expression. These results suggest that in arsenic-treated SVEC4-10 cells, HO-1 expression is mediated through Nrf2-, NF-κB-, and p38 MAPK-dependent signaling pathways and serves as an upstream regulator of VEGF. IL-6 expression is regulated by NF-κB and JNKs. In conclusion, oxidative stress may be associated with arsenic-induced cytotoxicity and endothelial gene up-regulation, but signaling transduction dominates the direct effects of ROS.
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan 701, Taiwan.
authors.forename: Lisu
authors.initials: L
authors.lastname: Wang
authors.forename: Mei-Chun
authors.initials: MC
authors.lastname: Kou
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Weng
authors.forename: Ling-Wei
authors.initials: LW
authors.lastname: Hu
authors.forename: Ying-Jan
authors.initials: YJ
authors.lastname: Wang
authors.forename: Ming-Jiuan
authors.initials: MJ
authors.lastname: Wu
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D002478:Cells, Cultured; D003603:Cytotoxins / Q000378:metabolism / Q000633:toxicity; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D012313:RNA / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014652:Vascular Diseases / Q000139:chemically induced* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D003603:Cytotoxins; D020672:I-kappa B Proteins; D015850:Interleukin-6; C000606205:Nfkbia protein, mouse; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D000072000:NF-KappaB Inhibitor alpha; D006418:Heme; D012313:RNA; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; D001151:Arsenic