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Title: Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite-Potential mechanism in the development of atherosclerosis

Abstract

Arsenic exposure has been shown to exacerbate atherosclerosis, beginning with activation of the endothelium that lines the vessel wall. Endothelial barrier integrity is maintained by proteins of the adherens junction (AJ) such as vascular endothelial cadherin (VE-cadherin) and {beta}-catenin and their association with the actin cytoskeleton. In the present study, human aortic endothelial cells (HAECs) were exposed to 1, 5 and 10 {mu}M sodium arsenite [As(III)] for 1, 6, 12 and 24 h, and the effects on endothelial barrier integrity were determined. Immunofluorescence studies revealed formation of actin stress fibers and non-uniform VE-cadherin and {beta}-catenin staining at cell-cell junctions that were concentration- and time-dependent. Intercellular gaps were observed with a measured increase in endothelial permeability. In addition, concentration-dependent increases in tyrosine phosphorylation (PY) of {beta}-catenin and activation of protein kinase C{alpha} (PKC{alpha}) were observed. Inhibition of PKC{alpha} restored VE-cadherin and {beta}-catenin staining at cell-cell junctions and abolished the As(III)-induced formation of actin stress fibers and intercellular gaps. Endothelial permeability and PY of {beta}-catenin were also reduced to basal levels. These results demonstrate that As(III) induces activation of PKC{alpha}, which leads to increased PY of {beta}-catenin downstream of PKC{alpha} activation. Phosphorylation of {beta}-catenin plausibly severs the association of VE-cadherin and {beta}-catenin,more » which along with formation of actin stress fibers, results in intercellular gap formation and increased endothelial permeability. To the best of our knowledge, this is the first report demonstrating that As(III) causes a loss of endothelial monolayer integrity, which potentially could contribute to the development of atherosclerosis.« less

Authors:
 [1];  [2];  [3]
  1. Department of Biomedical and Pharmaceutical Sciences and Center for Environmental Health Sciences, University of Montana, 32 Campus Drive, Missoula, MT 59812 (United States). E-mail: flavia.pereira@umontana.edu
  2. Department of Biomedical and Pharmaceutical Sciences and Center for Environmental Health Sciences, University of Montana, 32 Campus Drive, Missoula, MT 59812 (United States). E-mail: douglas.coffin@umontana.edu
  3. Department of Biomedical and Pharmaceutical Sciences and Center for Environmental Health Sciences, University of Montana, 32 Campus Drive, Missoula, MT 59812 (United States). E-mail: howard.beall@umontana.edu
Publication Date:
OSTI Identifier:
20976907
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 220; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2006.12.035; PII: S0041-008X(07)00003-8; Copyright (c) 2007 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; ACTIN; ARSENIC; ARTERIOSCLEROSIS; BIOLOGICAL STRESS; ENDOTHELIUM; FIBERS; INHIBITION; MICROTUBULES; PERMEABILITY; PHOSPHORYLATION; SODIUM; TIME DEPENDENCE; TYROSINE

Citation Formats

Pereira, Flavia E., Coffin, J. Douglas, and Beall, Howard D. Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite-Potential mechanism in the development of atherosclerosis. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.12.035.
Pereira, Flavia E., Coffin, J. Douglas, & Beall, Howard D. Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite-Potential mechanism in the development of atherosclerosis. United States. doi:10.1016/j.taap.2006.12.035.
Pereira, Flavia E., Coffin, J. Douglas, and Beall, Howard D. Sun . "Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite-Potential mechanism in the development of atherosclerosis". United States. doi:10.1016/j.taap.2006.12.035.
@article{osti_20976907,
title = {Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite-Potential mechanism in the development of atherosclerosis},
author = {Pereira, Flavia E. and Coffin, J. Douglas and Beall, Howard D.},
abstractNote = {Arsenic exposure has been shown to exacerbate atherosclerosis, beginning with activation of the endothelium that lines the vessel wall. Endothelial barrier integrity is maintained by proteins of the adherens junction (AJ) such as vascular endothelial cadherin (VE-cadherin) and {beta}-catenin and their association with the actin cytoskeleton. In the present study, human aortic endothelial cells (HAECs) were exposed to 1, 5 and 10 {mu}M sodium arsenite [As(III)] for 1, 6, 12 and 24 h, and the effects on endothelial barrier integrity were determined. Immunofluorescence studies revealed formation of actin stress fibers and non-uniform VE-cadherin and {beta}-catenin staining at cell-cell junctions that were concentration- and time-dependent. Intercellular gaps were observed with a measured increase in endothelial permeability. In addition, concentration-dependent increases in tyrosine phosphorylation (PY) of {beta}-catenin and activation of protein kinase C{alpha} (PKC{alpha}) were observed. Inhibition of PKC{alpha} restored VE-cadherin and {beta}-catenin staining at cell-cell junctions and abolished the As(III)-induced formation of actin stress fibers and intercellular gaps. Endothelial permeability and PY of {beta}-catenin were also reduced to basal levels. These results demonstrate that As(III) induces activation of PKC{alpha}, which leads to increased PY of {beta}-catenin downstream of PKC{alpha} activation. Phosphorylation of {beta}-catenin plausibly severs the association of VE-cadherin and {beta}-catenin, which along with formation of actin stress fibers, results in intercellular gap formation and increased endothelial permeability. To the best of our knowledge, this is the first report demonstrating that As(III) causes a loss of endothelial monolayer integrity, which potentially could contribute to the development of atherosclerosis.},
doi = {10.1016/j.taap.2006.12.035},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 220,
place = {United States},
year = {Sun Apr 15 00:00:00 EDT 2007},
month = {Sun Apr 15 00:00:00 EDT 2007}
}