H2O2-mediated permeability: role of MAPK and occludin

H2O2-mediated elevation in endothelial solute permeability is associated wi th pathological events such as ischemia-reperfusion and inflammation. To un derstand how H2O2 mediates increased permeability, we investigated the effe cts of H2O2 administration on vascular endothelial barrier properties and t ight junction organization and function. We report that H2O2 exposure cause d an increase in endothelial solute permeability in a time-dependent manner through extracellularly regulated kinase 1 and 2 (ERK1/ERK2) signal pathwa ys. H2O2 exposure caused the tight junctional protein occludin to be rearra nged from endothelial cell-cell junctions. Occludin rearrangement involved redistribution of occludin on the cell surface and dissociation of occludin from ZO-1. Occludin also was heavily phosphorylated on serine residues upo n H2O2 administration. H2O2 mediates changes in ERK1/ERK2 phosphorylation, increases endothelial solute permeability, and alters occludin localization and phosphorylation were all blocked by PD-98059, a specific mitogen-activ ated protein (MAP) or ERK kinase 1 inhibitor. These data strongly suggest t hat H2O2-mediated increased endothelial solute permeability involves the lo ss of endothelial tight junction integrity through increased ERK1/ERK2 acti vation.