H2O2-mediated permeability:: role of MAPK and occludin
H2O2-mediated permeability:: role of MAPK and occludin
复制标题
DOI：
10.1152/ajpcell.2000.279.1.c21
复制
发表时间：
2000-07-01
影响因子：
5.5
通讯作者：
Alexander, JS
中科院分区：
文献类型：
--
作者：
Kevil, CG;Oshima, T;Alexander, JS
h2o2介导的内皮溶质通透性升高与缺血-再灌注和炎症等病理事件有关。为了了解H2O2是如何介导通透性增加的，我们研究了H2O2对血管内皮屏障特性和紧密连接组织和功能的影响。我们报道H2O2暴露通过细胞外调节的激酶1和2 （ERK1/ERK2）信号通路以时间依赖性的方式引起内皮溶质通透性的增加。H2O2暴露导致紧密连接蛋白occludin从内皮细胞-细胞连接重排。Occludin重排包括Occludin在细胞表面的重新分布和Occludin与ZO-1的分离。在H2O2的作用下，Occludin在丝氨酸残基上也被严重磷酸化。H2O2介导ERK1/ERK2磷酸化的变化，增加内皮溶质通透性，改变occludin定位和磷酸化，这些都被PD-98059（一种特异性丝裂原活化蛋白（MAP）或ERK激酶1抑制剂）阻断。这些数据强烈表明h2o2介导的内皮溶质通透性增加涉及通过增加ERK1/ERK2激活内皮紧密连接完整性的丧失。
H2O2-mediated elevation in endothelial solute permeability is associated with pathological events such as ischemia-reperfusion and inflammation. To understand how H2O2 mediates increased permeability, we investigated the effects of H2O2 administration on vascular endothelial barrier properties and tight junction organization and function. We report that H2O2 exposure caused an increase in endothelial solute permeability in a time-dependent manner through extracellularly regulated kinase 1 and 2 (ERK1/ERK2) signal pathways. H2O2 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 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-activated protein (MAP) or ERK kinase 1 inhibitor. These data strongly suggest that H2O2-mediated increased endothelial solute permeability involves the loss of endothelial tight junction integrity through increased ERK1/ERK2 activation.