EETs Reduces LPS-induced Hyperpermeability by Targeting GRP78 Mediated Src Activation and Subsequent Rho/ROCK Signaling Pathway

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Sep 9

PMID 28881620

Citations 11

Authors

Ruolan Dong

Danli Hu

Yan Yang

Zhihui Chen

Menglu Fu

Dao Wen Wang

Xizhen Xu

Ling Tu

Affiliations

Soon will be listed here.

Abstract

Integrity of endothelial barrier is a determinant of the prognosis in the acute lung injury caused by sepsis. The epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, exhibit protective effects in various pathogenic states, however, whether EETs play a role in endothelial barrier enhancement and the involved mechanisms remain to be investigated. Here, we show that increased EETs level by endothelial specific cytochrome P450 epoxygenase 2J2 over-expression and soluble epoxide hydrolase (sEH) inhibitor TPPU reduced lipopolysaccharide-induced endothelial hyper-permeability , accompanied by improved survival of septic mice. In addition, sEH inhibitor AUDA and 11,12-EET also decreased endothelial hyper-permeability in the study. Importantly, the relative mechanisms were associated with reduced GRP78-Src interaction and ROS production, and subsequently reduced RhoA/ROCK activation, and eventually decreased VE-cadherin and myosin light chain (MLC) phosphorylation. Thus CYP2J2-EETs is crucial for RhoA-dependent regulation of cytoskeletal architecture leading to reversible changes in vascular permeability, which may contribute to the development of new therapeutic approaches for pulmonary edema and other diseases caused by abnormal vascular permeability.

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