Arsenite Acutely Decreases Nitric Oxide Production via the ROS-Protein Phosphatase 1-Endothelial Nitric Oxide Synthase-Thr497 Signaling Cascade.
10.4062/biomolther.2014.106
- Author:
Jungwon SEO
1
;
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
Author Information
1. Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea. inhojo@ewha.ac.kr
- Publication Type:Original Article
- Keywords:
Arsenite;
Vascular disease;
Nitric oxide;
Endothelial nitric oxide synthase;
Reactive oxygen species;
Protein phosphatase 1
- MeSH:
Acetylcysteine;
Endothelial Cells;
Nitric Oxide Synthase;
Nitric Oxide Synthase Type III;
Nitric Oxide*;
Phosphorylation;
Protein Isoforms;
Protein Kinase C;
Protein Phosphatase 1;
Reactive Oxygen Species;
Serine;
Vascular Diseases
- From:Biomolecules & Therapeutics
2014;22(6):510-518
- CountryRepublic of Korea
- Language:English
-
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 (eNOS-Ser1179 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 eNOS-Thr497, but not of eNOS-Ser116 or 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 eNOS-Thr497 phosphorylation. Although protein kinase C (PKC) and protein phosphatase 1 (PP1) were reported to be involved in eNOS-Thr497 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.
