H(2)O(2)-mediated permeability: role of MAPK and occludin.
H(2)O(2)-mediated elevation in endothelial solute permeability is associated with pathological events such as ischemia-reperfusion and inflammation. To understand how H(2)O(2) mediates increased permeability, we investigated the effects of H(2)O(2) administration on vascular endothelial barrier properties and tight junction organization and function. We report that H(2)O(2) exposure caused an increase in endothelial solute permeability in a time-dependent manner through extracellularly regulated kinase 1 and 2 (ERK1/ERK2) signal pathways. H(2)O(2) exposure caused the tight junctional protein occludin to be rearranged 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 upon H(2)O(2) administration. H(2)O(2) 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-activated protein (MAP) or ERK kinase 1 inhibitor. These data strongly suggest that H(2)O(2)-mediated increased endothelial solute permeability involves the loss of endothelial tight junction integrity through increased ERK1/ERK2 activation.
Kevil
C G
CG
Department of Molecular and Cellular Physiology, Louisiana State University Medical Center Shreveport, 1501 Kings Highway, Shreveport, Louisiana 71130, USA.
Oshima
T
T
Alexander
B
B
Coe
L L
LL
Alexander
J S
JS
D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004705:Endocytosis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D014018:Tissue Distribution; D062826:Zonula Occludens-1 Protein
D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D012694:Serine; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases