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Title: Arsenite induces endothelial cytotoxicity by down-regulation of vascular endothelial nitric oxide synthase

Abstract

Epidemiological studies have demonstrated a high association of inorganic arsenic exposure with vascular diseases. Recent research has also linked this vascular damage to impairment of endothelial nitric oxide synthase (eNOS) function by arsenic exposure. However, the role of eNOS in regulating the arsenite-induced vascular dysfunction still remains to be clarified. In our present study, we investigated the effect of arsenite on Akt1 and eNOS and its involvement in cytotoxicity of vascular endothelial cells. Our study demonstrated that arsenite decreased the protein levels of both Akt1 and eNOS accompanied with increased levels of ubiquitination of total cell lysates. We found that inhibition of the ubiquitin-proteasome pathway by MG-132 could partially protect Akt1 and eNOS from degradation by arsenite together with a proportional protection from the arsenite-induced cytoxicity. Moreover, up-regulation of eNOS protein expression significantly attenuated the arsenite-induced cytotoxicity and eNOS activity could be significantly inhibited after incubation with arsenite for 24 h in a cell-free system. Our study indicated that endothelial eNOS activity could be attenuated by arsenite via the ubiquitin-proteasome-mediated degradation of Akt1/eNOS as well as via direct inhibition of eNOS activity. Our study also demonstrated that eNOS actually played a protective role in arsenite-induced cytoxicity. These observations supported themore » hypothesis that the impairment of eNOS function by arsenite is one of the mechanisms leading to vascular changes and diseases.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [2]
  1. Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 100 Shih-Chuan 1st Road, Kaohsiung 807 (China). E-mail: tctsou@nhri.org.tw
  2. Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 100 Shih-Chuan 1st Road, Kaohsiung 807 (China)
Publication Date:
OSTI Identifier:
20722028
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 208; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2005.03.001; PII: S0041-008X(05)00113-4; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ARSENIC; DAMAGE; ENDOTHELIUM; INCUBATION; INHIBITION; NITRIC OXIDE; PROTEINS; SAFETY; TOXICITY; VASCULAR DISEASES

Citation Formats

Tsou, T.-C., Tsai, F.-Y., Hsieh, Y.-W., Li, L.-A., Yeh, S.C, and Chang, L.W. Arsenite induces endothelial cytotoxicity by down-regulation of vascular endothelial nitric oxide synthase. United States: N. p., 2005. Web. doi:10.1016/j.taap.2005.03.001.
Tsou, T.-C., Tsai, F.-Y., Hsieh, Y.-W., Li, L.-A., Yeh, S.C, & Chang, L.W. Arsenite induces endothelial cytotoxicity by down-regulation of vascular endothelial nitric oxide synthase. United States. doi:10.1016/j.taap.2005.03.001.
Tsou, T.-C., Tsai, F.-Y., Hsieh, Y.-W., Li, L.-A., Yeh, S.C, and Chang, L.W. Tue . "Arsenite induces endothelial cytotoxicity by down-regulation of vascular endothelial nitric oxide synthase". United States. doi:10.1016/j.taap.2005.03.001.
@article{osti_20722028,
title = {Arsenite induces endothelial cytotoxicity by down-regulation of vascular endothelial nitric oxide synthase},
author = {Tsou, T.-C. and Tsai, F.-Y. and Hsieh, Y.-W. and Li, L.-A. and Yeh, S.C and Chang, L.W.},
abstractNote = {Epidemiological studies have demonstrated a high association of inorganic arsenic exposure with vascular diseases. Recent research has also linked this vascular damage to impairment of endothelial nitric oxide synthase (eNOS) function by arsenic exposure. However, the role of eNOS in regulating the arsenite-induced vascular dysfunction still remains to be clarified. In our present study, we investigated the effect of arsenite on Akt1 and eNOS and its involvement in cytotoxicity of vascular endothelial cells. Our study demonstrated that arsenite decreased the protein levels of both Akt1 and eNOS accompanied with increased levels of ubiquitination of total cell lysates. We found that inhibition of the ubiquitin-proteasome pathway by MG-132 could partially protect Akt1 and eNOS from degradation by arsenite together with a proportional protection from the arsenite-induced cytoxicity. Moreover, up-regulation of eNOS protein expression significantly attenuated the arsenite-induced cytotoxicity and eNOS activity could be significantly inhibited after incubation with arsenite for 24 h in a cell-free system. Our study indicated that endothelial eNOS activity could be attenuated by arsenite via the ubiquitin-proteasome-mediated degradation of Akt1/eNOS as well as via direct inhibition of eNOS activity. Our study also demonstrated that eNOS actually played a protective role in arsenite-induced cytoxicity. These observations supported the hypothesis that the impairment of eNOS function by arsenite is one of the mechanisms leading to vascular changes and diseases.},
doi = {10.1016/j.taap.2005.03.001},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 208,
place = {United States},
year = {Tue Nov 01 00:00:00 EST 2005},
month = {Tue Nov 01 00:00:00 EST 2005}
}