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1 Department of Genomics and Pathobiology, University of Alabama Birmingham, Birmingham, Alabama 35294; and 2 Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130
We previously reported
that exposure of endothelial cells to H2O2
results in a loss of cell-cell apposition and increased endothelial
solute permeability. The purpose of this study was to determine how
tyrosine phosphorylation and tyrosine phosphatases contribute to
oxidant-mediated disorganization of endothelial cell junctions. We
found that H2O2 caused a rapid decrease in total cellular phosphatase activity that facilitates a compensatory increase in cellular phosphotyrosine residues.
H2O2 exposure also results in increased
endothelial monolayer permeability, which was attenuated by pp60, an
inhibitor of src kinase. Inhibition of protein tyrosine
phosphatase activity by phenylarsine oxide (PAO) demonstrated a similar
permeability profile compared with H2O2,
suggesting that tyrosine phosphatase activity is important in
maintaining a normal endothelial solute barrier. Immunofluorescence shows that H2O2 exposure caused a loss of
pan-reactive cadherin and 
-catenin from cell junctions that was not
blocked by the src kinase inhibitor PP1.
H2O2 also caused -catenin to dissociate from
the endothelial cytoskeleton, which was not prevented by PP1. Finally,
we determined that PP1 did not prevent cadherin internalization. These
data suggest that oxidants like H2O2 produce biological effects through protein phosphotyrosine modifications by
decreasing total cellular phosphatase activity combined with increased
src kinase activity, resulting in increased endothelial solute permeability.
solute permeability; src kinase; cadherin; catenin
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