H₂O₂-mediated permeability: role of MAPK and occludin

Abstract

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.

Reassembly of the Tight Junction after Oxidative Stress Depends on Tyrosine Kinase Activity

“…During disassembly of the junctional complex, occludin was found to be serine/threonine phosphorylated in endothelial cells after exposure to oxidative stress (15). Other studies in Strong tyrosine phosphorylation in the same region also occurred during the recovery period (f) which was diminished in the PP-2 and genistein-treated monolayers (d and e, same samples as shown in Fig.…”

“…Reported effects of hydrogen peroxide on renal epithelial cell lines include DNA damage with induction of apoptosis or necrosis (1-3), decreased activity of membrane transporters (4), and membrane lipid peroxidation (5). Hydrogen peroxide decreases transepithelial resistance (TER) and increases transcellular permeability of MDCK cell monolayers (6,7), which is also well documented in non-kidney epithelial cell lines (8 -11) and endothelial cell lines (12)(13)(14)(15). However, the biochemical and subcellular effects of hydrogen peroxide on tight junction (TJ) proteins have not been studied, nor have they been distinguished from effects due to partial ATP depletion.…”

Calcium influx-dependent differential actions of superoxide and hydrogen peroxide on microvessel permeability

“…Hydroxyl radicals derived from superoxide anions have been reported as a key factor in increased vascular permeability produced by ischemia and systemic infusion or local superfusion of HX/XO (7,28,29 ] i and permeability indicate that these two ROS may trigger signaling pathways or evoke cellular damage via different cellular mechanisms. Currently, in vitro studies indicate that endothelial gap formation, the disruption of adhesion proteins, and the changes in cytoskeleton arrangements are the mechanisms for ROS-induced endothelial barrier dysfunction, which are similar to those reported in inflammatory mediator-induced permeability increases (1,9,12,17,20,21,36). Whether different cellular mechanisms are responsible for such distinct patterns of permeability increases in intact microvessels remains to be determined.…”

Mitogen-Activated Protein Kinase Inhibition and Cardioplegia-Cardiopulmonary Bypass Reduce Coronary Myogenic Tone

“…ERK1/2 has been implicated in several physiological processes including cytokine production 11 and vascular endothelial cell permeability. 12 Specifically, the ERK1/2 pathway has been shown to regulate coronary vascular smooth muscle cell contraction. 13,14 In our study, treatment of coronary arterioles with PD98059, the MEK1/2 inhibitor, resulted in decreased myogenic tone.…”