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KMID : 0606920140220060510
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Biomolecules & Therapeutics
2014 Volume.22 No. 6 p.510 ~ p.518
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Arsenite Acutely Decreases Nitric Oxide Production via the ROS?Protein Phosphatase 1?Endothelial Nitric Oxide Synthase-Thr497 Signaling Cascade
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Seo Jung-Won
Lee Jee-Young
Sung Min-Sun
Byun Jeong-Hae
Cho Du-Hyong
Lee Hyeon-Ju
Park Jung-Hyun
Cho Ho-Seong
Cho Sung-Jin
Jo In-Ho
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Abstract
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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.
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KEYWORD
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Arsenite, Vascular disease, Nitric oxide, Endothelial nitric oxide synthase, Reactive oxygen species, Protein phosphatase 1
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