Open AccessWild‐type p53 enhances endothelial barrier function by mediating RAC 1 signalling and RhoA inhibition
Author(s) -
Barabutis Nektarios,
Dimitropoulou Christiana,
Gregory Betsy,
Catravas John D.
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13460
Subject(s) - rhoa , cofilin , barrier function , rac1 , microbiology and biotechnology , endothelium , biology , vascular permeability , phosphorylation , gene silencing , endothelial stem cell , rac gtp binding proteins , cancer research , immunology , signal transduction , endocrinology , biochemistry , cell , actin cytoskeleton , in vitro , gene , cytoskeleton
Inflammation is the major cause of endothelial barrier hyper‐permeability, associated with acute lung injury and acute respiratory distress syndrome. This study reports that p53 “orchestrates” the defence of vascular endothelium against LPS , by mediating the opposing actions of Rac1 and RhoA in pulmonary tissues. Human lung microvascular endothelial cells treated with HSP 90 inhibitors activated both Rac1‐ and P21‐activated kinase, which is an essential element of vascular barrier function. 17 AAG increased the phosphorylation of both LIMK and cofilin, in contrast to LPS which counteracted those effects. Mouse lung microvascular endothelial cells exposed to LPS exhibited decreased expression of phospho‐cofilin. 17 AAG treatment resulted in reduced levels of active cofilin. Silencing of cofilin pyridoxal phosphate phosphatase ( PDXP ) blocked the LPS ‐induced hyper‐permeability, and P53 inhibition reversed the 17 AAG ‐induced PDXP down‐regulation. P190 RHOGAP suppression enhanced the LPS ‐triggered barrier dysfunction in endothelial monolayers. 17 AAG treatment resulted in P190 RHOGAP induction and blocked the LPS ‐induced pMLC 2 up‐regulation in wild‐type mice. Pulmonary endothelial cells from “super p53” mice, which carry additional p53‐tg alleles, exhibited a lower response to LPS than the controls. Collectively, our findings help elucidate the mechanisms by which p53 operates to enhance barrier function.