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Media type:
E-Article
Title:
Wild‐type p53 enhances endothelial barrier function by mediating RAC1 signalling and RhoA inhibition
Contributor:
Barabutis, Nektarios;
Dimitropoulou, Christiana;
Gregory, Betsy;
Catravas, John D.
imprint:
Wiley, 2018
Published in:Journal of Cellular and Molecular Medicine
Language:
English
DOI:
10.1111/jcmm.13460
ISSN:
1582-1838;
1582-4934
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:p>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 <jats:styled-content style="fixed-case">LPS</jats:styled-content>, by mediating the opposing actions of Rac1 and RhoA in pulmonary tissues. Human lung microvascular endothelial cells treated with <jats:styled-content style="fixed-case">HSP</jats:styled-content>90 inhibitors activated both Rac1‐ and P21‐activated kinase, which is an essential element of vascular barrier function. 17<jats:styled-content style="fixed-case">AAG</jats:styled-content> increased the phosphorylation of both <jats:styled-content style="fixed-case">LIMK</jats:styled-content> and cofilin, in contrast to <jats:styled-content style="fixed-case">LPS</jats:styled-content> which counteracted those effects. Mouse lung microvascular endothelial cells exposed to <jats:styled-content style="fixed-case">LPS</jats:styled-content> exhibited decreased expression of phospho‐cofilin. 17<jats:styled-content style="fixed-case">AAG</jats:styled-content> treatment resulted in reduced levels of active cofilin. Silencing of cofilin pyridoxal phosphate phosphatase (<jats:styled-content style="fixed-case">PDXP</jats:styled-content>) blocked the <jats:styled-content style="fixed-case">LPS</jats:styled-content>‐induced hyper‐permeability, and P53 inhibition reversed the 17<jats:styled-content style="fixed-case">AAG</jats:styled-content>‐induced <jats:styled-content style="fixed-case">PDXP</jats:styled-content> down‐regulation. P190<jats:styled-content style="fixed-case">RHOGAP</jats:styled-content> suppression enhanced the <jats:styled-content style="fixed-case">LPS</jats:styled-content>‐triggered barrier dysfunction in endothelial monolayers. 17<jats:styled-content style="fixed-case">AAG</jats:styled-content> treatment resulted in P190<jats:styled-content style="fixed-case">RHOGAP</jats:styled-content> induction and blocked the <jats:styled-content style="fixed-case">LPS</jats:styled-content>‐induced <jats:styled-content style="fixed-case">pMLC</jats:styled-content>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 <jats:styled-content style="fixed-case">LPS</jats:styled-content> than the controls. Collectively, our findings help elucidate the mechanisms by which p53 operates to enhance barrier function.</jats:p>