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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 microM 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 Calpha (PKCalpha) were observed. Inhibition of PKCalpha 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 PKCalpha, which leads to increased PY of beta-catenin downstream of PKCalpha 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.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Pereira FE,Coffin JD,Beall HD

doi

10.1016/j.taap.2006.12.035

subject

Has Abstract

pub_date

2007-04-15 00:00:00

pages

164-77

issue

eissn

0041-008X

issn

1096-0333

pii

S0041-008X(07)00003-8

journal_volume

220

pub_type

杂志文章

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