Wild-Type p53 Enhances Endothelial Barrier Function by Mediating RAC1 Signalling and RhoA Inhibition
Document Type
Article
Publication Date
2018
Publication Title
Journal of Cellular and Molecular Medicine
Volume
20
Issue
10
Pages
1-13
DOI
10.1111/jcmm.13460
Abstract
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 HSP90 inhibitors activated both Rac1- and P21-activated kinase, which is an essential element of vascular barrier function. 17AAG 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. 17AAG 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 17AAG-induced PDXP down-regulation. P190RHOGAP suppression enhanced the LPS-triggered barrier dysfunction in endothelial monolayers. 17AAG treatment resulted in P190RHOGAP induction and blocked the LPS-induced pMLC2 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.
Original Publication Citation
Barabutis, N., Dimitropoulou, C., Gregory, B., & Catravas, J. D. (2018). Wild-type p53 enhances endothelial barrier function by mediating RAC1 signalling and RhoA inhibition. Journal of Cellular and Molecular Medicine, 20(10), 1-13. doi:10.1111/jcmm.13460
Repository Citation
Barabutis, Nektarios; Dimitropoulou, Christiana; Gregory, Betsy; and Catravas, John D., "Wild-Type p53 Enhances Endothelial Barrier Function by Mediating RAC1 Signalling and RhoA Inhibition" (2018). Bioelectrics Publications. 148.
https://digitalcommons.odu.edu/bioelectrics_pubs/148
ORCID
0000-0002-9663-5662 (Barabutis), 0000-0002-5098-295X (Catravas)
Included in
Cell Biology Commons, Diseases Commons, Genetics Commons, Molecular Biology Commons, Molecular, Cellular, and Tissue Engineering Commons
Comments
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.