PMID- 22488045
OWN - NLM
STAT- MEDLINE
DCOM- 20121018
LR  - 20211025
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Linking)
VI  - 86
IP  - 6
DP  - 2012 Jun
TI  - Arsenic modulates heme oxygenase-1, interleukin-6, and vascular endothelial 
      growth factor expression in endothelial cells: roles of ROS, NF-kappaB, and MAPK 
      pathways.
PG  - 879-96
LID - 10.1007/s00204-012-0845-z [doi]
AB  - 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 alpha-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-kappaB (NF-kappaB). 
      NF-kappaB 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-kappaB-, and p38 MAPK-dependent 
      signaling pathways and serves as an upstream regulator of VEGF. IL-6 expression 
      is regulated by NF-kappaB 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.
FAU - Wang, Lisu
AU  - Wang L
AD  - Department of Environmental and Occupational Health, National Cheng Kung 
      University Medical College, Tainan 701, Taiwan.
FAU - Kou, Mei-Chun
AU  - Kou MC
FAU - Weng, Ching-Yi
AU  - Weng CY
FAU - Hu, Ling-Wei
AU  - Hu LW
FAU - Wang, Ying-Jan
AU  - Wang YJ
FAU - Wu, Ming-Jiuan
AU  - Wu MJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120410
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 0 (Cytotoxins)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Interleukin-6)
RN  - 0 (Nfkbia protein, mouse)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - 42VZT0U6YR (Heme)
RN  - 63231-63-0 (RNA)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - N712M78A8G (Arsenic)
SB  - IM
MH  - Animals
MH  - Arsenic/*toxicity
MH  - Cells, Cultured
MH  - Cytotoxins/metabolism/toxicity
MH  - Endothelial Cells/*drug effects/metabolism
MH  - Enzyme Activation/drug effects
MH  - Gene Expression Regulation/drug effects
MH  - Heme/*metabolism
MH  - Heme Oxygenase-1/genetics/*metabolism
MH  - I-kappa B Proteins/metabolism
MH  - Interleukin-6/genetics/*metabolism
MH  - Mice
MH  - NF-KappaB Inhibitor alpha
MH  - RNA/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/drug effects
MH  - Up-Regulation/drug effects
MH  - Vascular Diseases/*chemically induced/metabolism
MH  - Vascular Endothelial Growth Factor A/genetics/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
EDAT- 2012/04/11 06:00
MHDA- 2012/10/19 06:00
CRDT- 2012/04/11 06:00
PHST- 2012/02/16 00:00 [received]
PHST- 2012/03/14 00:00 [accepted]
PHST- 2012/04/11 06:00 [entrez]
PHST- 2012/04/11 06:00 [pubmed]
PHST- 2012/10/19 06:00 [medline]
AID - 10.1007/s00204-012-0845-z [doi]
PST - ppublish
SO  - Arch Toxicol. 2012 Jun;86(6):879-96. doi: 10.1007/s00204-012-0845-z. Epub 2012 
      Apr 10.