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Monomethylarsonous Acid Induced Cytotoxicity and Endothelial Nitric Oxide Synthase Phosphorylation in Endothelial Cells

  • B. Li
  • Y.  Sun
  • X. Sun
  • Y. Wang
  • X. Li
  • Y. Kumagai
  • G. Sun
Article

Abstract

Chronic arsenic poisoning is reported to be associated with peripheral and cardiovascular disease, arteriosclerosis, Raynaud’s syndrome, hypertension, and Blackfoot disease. Monomethylarsonous acid (MMAIII) is a reactive metabolite of inorganic arsenic and a potent inhibitor of endothelial nitric oxide synthase (eNOS). Arsenic is also reported to phosphorylate eNOS in cultured keratinocyte and Human T cell leukemia Jurkat cells, respectively. In the present study, we examined the cytotoxicity and eNOS phosphorylation by MMAIII exposure in cultured bovine aortic endothelial cells (BAEC). Results showed that MMAIII is more toxic than arsenite in BAEC cells. The IC50 values for MMAIII and arsenite were determined to be approximately 1.7 and 24.1 μmol/L, respectively. Exposure of BAEC to MMAIII (0.75 μmol/L) caused a significant eNOS phosphorylation 15 min after MMAIII exposure. However, a complex of MMAIII with dithiothreitol (DTT) that lacks the reactivity with vicinal thiols unaffected eNOS phosphorylation. The present study shows that MMAIII generated during biomethylation of arsenic is highly toxic in BAEC. Our study also suggests that MMAIII could induce the eNOS phosphorylation through modification to cellular thiols of the eNOS enzyme. And the initial up-regulation of eNOS phosphorylation by MMAIII seems to be an adaptive response against disruption of eNOS bioactivity during arsenic exposure.

Keywords

monomethylarsonous acid (MMAIIIarsenic endothelial nitric oxide synthase (eNOS) phosphorylation endothelial cell 

Notes

Acknowledgments

This study was supported by the National Natural Science Foundation of China (NSFC) research grant 30400362, 30530640 & 30600510, and also supported in part by the Japan-China Sasagawa Medical Fellowship. We are especially grateful to Dr. William R. Cullen for providing MMAIII.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • B. Li
    • 1
  • Y.  Sun
    • 2
  • X. Sun
    • 3
  • Y. Wang
    • 1
  • X. Li
    • 1
  • Y. Kumagai
    • 2
  • G. Sun
    • 1
  1. 1.Department of Occupational and Environmental Health, School of Public HealthChina Medical UniversityShenyangChina
  2. 2.Doctoral Programs in Medical SciencesUniversity of TsukubaTsukubaJapan
  3. 3.Hygiene DepartmentCollege of Basic Medical Sciences, Dalian Medical UniversityDalianChina

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