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

• Published in: Toxicology and applied pharmacology Vol. 208; no. 3; pp. 277 - 284
• Main Authors: Tsou, Tsui-Chun, Tsai, Feng-Yuan, Hsieh, Yao-Wen, Li, Lih-Ann, Yeh, Szu Ching, Chang, Louis W.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01-11-2005; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Androstadienes - administration & dosage; Animals; Aorta, Thoracic - pathology; ARSENIC; Arsenite; Arsenites - antagonists & inhibitors; Arsenites - toxicity; Biological and medical sciences; Cell Line; Cell Survival - drug effects; Chemical and industrial products toxicology. Toxic occupational diseases; Chromones - administration & dosage; DAMAGE; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Endothelial Cells - chemistry; Endothelial Cells - drug effects; Endothelial Cells - pathology; ENDOTHELIUM; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Endothelium, Vascular - physiology; eNOS; INCUBATION; INHIBITION; Leupeptins - pharmacology; Medical sciences; Metals and various inorganic compounds; Morpholines - administration & dosage; NITRIC OXIDE; Nitric Oxide Synthase Type III - antagonists & inhibitors; Nitric Oxide Synthase Type III - drug effects; Nitric Oxide Synthase Type III - metabolism; Phosphatidylinositol 3-Kinases - administration & dosage; Phosphorylation; Proteasome; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - metabolism; PROTEINS; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - chemistry; Proto-Oncogene Proteins c-akt - metabolism; SAFETY; Sodium Compounds - antagonists & inhibitors; Sodium Compounds - toxicity; Swine; Time Factors; TOXICITY; Toxicology; Up-Regulation; VASCULAR DISEASES; Vascular endothelium; Vascular endothelium; eNOS; Arsenite; Proteasome; Multicatalytic endopeptidase complex; Endothelial cell; Enzyme; Cytotoxicity; Nitric-oxide synthase; Arsenite; Vascular endothelium; eNOS; Arsenites; Endothelium; Peptidases; Blood vessel; Hydrolases; Circulatory system; Oxidoreductases
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2005.03.001

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.