Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/95048
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Type: Journal article
Title: Preconditioning with endoplasmic reticulum stress ameliorates endothelial cell inflammation
Author: Leonard, A.
Paton, A.
El-Quadi, M.
Paton, J.
Fazal, F.
Citation: PLoS One, 2014; 9(10):e110949-1-e110949-18
Publisher: Public Library of Science
Issue Date: 2014
ISSN: 1932-6203
1932-6203
Statement of
Responsibility: 
Antony Leonard, Adrienne W. Paton, Monaliza El-Quadi, James C. Paton, Fabeha Fazal
Abstract: Endoplasmic Reticulum (ER) stress, caused by disturbance in ER homeostasis, has been implicated in several pathological conditions such as ischemic injury, neurodegenerative disorders, metabolic diseases and more recently in inflammatory conditions. Our present study aims at understanding the role of ER stress in endothelial cell (EC) inflammation, a critical event in the pathogenesis of acute lung injury (ALI). We found that preconditioning human pulmonary artery endothelial cells (HPAEC) to ER stress either by depleting ER chaperone and signaling regulator BiP using siRNA, or specifically cleaving (inactivating) BiP using subtilase cytotoxin (SubAB), alleviates EC inflammation. The two approaches adopted to abrogate BiP function induced ATF4 protein expression and the phosphorylation of eIF2α, both markers of ER stress, which in turn resulted in blunting the activation of NF-κB, and restoring endothelial barrier integrity. Pretreatment of HPAEC with BiP siRNA inhibited thrombin-induced IκBα degradation and its resulting downstream signaling pathway involving NF-κB nuclear translocation, DNA binding, phosphorylation at serine536, transcriptional activation and subsequent expression of adhesion molecules. However, TNFα-mediated NF-κB signaling was unaffected upon BiP knockdown. In an alternative approach, SubAB-mediated inactivation of NF-κB was independent of IκBα degradation. Mechanistic analysis revealed that pretreatment of EC with SubAB interfered with the binding of the liberated NF-κB to the DNA, thereby resulting in reduced expression of adhesion molecules, cytokines and chemokines. In addition, both knockdown and inactivation of BiP stimulated actin cytoskeletal reorganization resulting in restoration of endothelial permeability. Together our studies indicate that BiP plays a central role in EC inflammation and injury via its action on NF-κB activation and regulation of vascular permeability.
Keywords: Pulmonary Artery; Cells, Cultured; Cytoskeleton; Endothelial Cells; Humans; Inflammation; Subtilisins; Tumor Necrosis Factor-alpha; Escherichia coli Proteins; NF-kappa B; Heat-Shock Proteins; Prokaryotic Initiation Factor-2; Phosphorylation; Acute Lung Injury; Endoplasmic Reticulum Stress
Rights: © 2014 Leonard et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
RMID: 0030014531
DOI: 10.1371/journal.pone.0110949
Appears in Collections:Molecular and Biomedical Science publications

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