Arsenite acutely decreases nitric oxide production via the ROS—protein phosphatase 1—endothelial nitric oxide synthase-thr497 signaling cascade

Jungwon Seo, Jee Young Lee, Min Sun Sung, Catherine Jeonghae Byun, Du Hyong Cho, Hyeon Ju Lee, Jung Hyun Park, Ho Seong Cho, Sung Jin Cho, Inho Jo

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Chronic (>24 h) exposure of arsenite, an environmental toxicant, has shown the decreased nitric oxide (NO) production in endothelial cells (EC) by decreasing endothelial NO synthase (eNOS) expression and/or its phosphorylation at serine 1179 (eNOSSer1179 in bovine sequence), which is associated with increased risk of vascular diseases. Here, we investigated the acute (<24 h) effect of arsenite on NO production using bovine aortic EC (BAEC). Arsenite acutely increased the phosphorylation of eNOSThr497, but not of eNOS-Ser116or eNOS-Ser1179, which was accompanied by decreased NO production. The level of eNOS expression was unaltered under this condition. Treatment with arsenite also induced reactive oxygen species (ROS) production, and pretreatment with a ROS scavenger N-acetyl-L-cysteine (NAC) completely reversed the observed effect of arsenite on eNOSThr497 phosphorylation. Although protein kinase C (PKC) and protein phosphatase 1 (PP1) were reported to be involved in eNOSThr497 phosphorylation, treatment with PKC inhibitor, Ro318425, and overexpression of various PKC isoforms did not affect the arsenite-stimulated eNOS-Thr497 phosphorylation. In contrast, treatment with PP1 inhibitor, calyculin A, mimicked the observed effect of arsenite on eNOS-Thr497 phosphorylation. Lastly, we found decreased cellular PP1 activity in arsenite-treated cells, which was reversed by NAC. Overall, our study demonstrates firstly that arsenite acutely decreases NO production at least in part by increasing eNOS-Thr497 phosphorylation via ROS-PP1 signaling pathway, which provide the molecular mechanism underlying arsenite-induced increase in vascular disease.

Original languageEnglish
Pages (from-to)510-518
Number of pages9
JournalBiomolecules and Therapeutics
Volume22
Issue number6
DOIs
StatePublished - 1 Nov 2014

Keywords

  • Arsenite
  • Endothelial nitric oxide synthase
  • Nitric oxide
  • Protein phosphatase 1
  • Reactive oxygen species
  • Vascular disease

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