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Role of Integrin β4 in Lung Endothelial Cell Inflammatory Responses to Mechanical Stress
Simvastatin, an HMG-CoA reductase inhibitor, has lung vascular-protective effects that are associated with decreased agonist-induced integrin β4 (ITGB4) tyrosine phosphorylation. Accordingly, we hypothesized that endothelial cell (EC) protection by simvastatin is dependent on these effects and sough...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647208/ https://www.ncbi.nlm.nih.gov/pubmed/26572585 http://dx.doi.org/10.1038/srep16529 |
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author | Chen, Weiguo Epshtein, Yulia Ni, Xiuquin Dull, Randal O. Cress, Anne E. Garcia, Joe G.N. Jacobson, Jeffrey R. |
author_facet | Chen, Weiguo Epshtein, Yulia Ni, Xiuquin Dull, Randal O. Cress, Anne E. Garcia, Joe G.N. Jacobson, Jeffrey R. |
author_sort | Chen, Weiguo |
collection | PubMed |
description | Simvastatin, an HMG-CoA reductase inhibitor, has lung vascular-protective effects that are associated with decreased agonist-induced integrin β4 (ITGB4) tyrosine phosphorylation. Accordingly, we hypothesized that endothelial cell (EC) protection by simvastatin is dependent on these effects and sought to further characterize the functional role of ITGB4 as a mediator of EC protection in the setting of excessive mechanical stretch at levels relevant to ventilator-induced lung injury (VILI). Initially, early ITGB4 tyrosine phosphorylation was confirmed in human pulmonary artery EC subjected to excessive cyclic stretch (18% CS). EC overexpression of mutant ITGB4 with specific tyrosines mutated to phenylalanine (Y1440, Y1526 Y1640, or Y1422) resulted in significantly attenuated CS-induced cytokine expression (IL6, IL-8, MCP-1, and RANTES). In addition, EC overexpression of ITGB4 constructs with specific structural deletions also resulted in significantly attenuated CS-induced inflammatory cytokine expression compared to overexpression of wildtype ITGB4. Finally, mice expressing a mutant ITGB4 lacking a cytoplasmic signaling domain were found to have attenuated lung injury after VILI-challenge (V(T) = 40 ml/kg, 4 h). Our results provide mechanistic insights into the anti-inflammatory properties of statins and may ultimately lead to novel strategies targeted at ITGB4 signaling to treat VILI. |
format | Online Article Text |
id | pubmed-4647208 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46472082015-11-23 Role of Integrin β4 in Lung Endothelial Cell Inflammatory Responses to Mechanical Stress Chen, Weiguo Epshtein, Yulia Ni, Xiuquin Dull, Randal O. Cress, Anne E. Garcia, Joe G.N. Jacobson, Jeffrey R. Sci Rep Article Simvastatin, an HMG-CoA reductase inhibitor, has lung vascular-protective effects that are associated with decreased agonist-induced integrin β4 (ITGB4) tyrosine phosphorylation. Accordingly, we hypothesized that endothelial cell (EC) protection by simvastatin is dependent on these effects and sought to further characterize the functional role of ITGB4 as a mediator of EC protection in the setting of excessive mechanical stretch at levels relevant to ventilator-induced lung injury (VILI). Initially, early ITGB4 tyrosine phosphorylation was confirmed in human pulmonary artery EC subjected to excessive cyclic stretch (18% CS). EC overexpression of mutant ITGB4 with specific tyrosines mutated to phenylalanine (Y1440, Y1526 Y1640, or Y1422) resulted in significantly attenuated CS-induced cytokine expression (IL6, IL-8, MCP-1, and RANTES). In addition, EC overexpression of ITGB4 constructs with specific structural deletions also resulted in significantly attenuated CS-induced inflammatory cytokine expression compared to overexpression of wildtype ITGB4. Finally, mice expressing a mutant ITGB4 lacking a cytoplasmic signaling domain were found to have attenuated lung injury after VILI-challenge (V(T) = 40 ml/kg, 4 h). Our results provide mechanistic insights into the anti-inflammatory properties of statins and may ultimately lead to novel strategies targeted at ITGB4 signaling to treat VILI. Nature Publishing Group 2015-11-17 /pmc/articles/PMC4647208/ /pubmed/26572585 http://dx.doi.org/10.1038/srep16529 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Chen, Weiguo Epshtein, Yulia Ni, Xiuquin Dull, Randal O. Cress, Anne E. Garcia, Joe G.N. Jacobson, Jeffrey R. Role of Integrin β4 in Lung Endothelial Cell Inflammatory Responses to Mechanical Stress |
title | Role of Integrin β4 in Lung Endothelial Cell Inflammatory Responses to Mechanical Stress |
title_full | Role of Integrin β4 in Lung Endothelial Cell Inflammatory Responses to Mechanical Stress |
title_fullStr | Role of Integrin β4 in Lung Endothelial Cell Inflammatory Responses to Mechanical Stress |
title_full_unstemmed | Role of Integrin β4 in Lung Endothelial Cell Inflammatory Responses to Mechanical Stress |
title_short | Role of Integrin β4 in Lung Endothelial Cell Inflammatory Responses to Mechanical Stress |
title_sort | role of integrin β4 in lung endothelial cell inflammatory responses to mechanical stress |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647208/ https://www.ncbi.nlm.nih.gov/pubmed/26572585 http://dx.doi.org/10.1038/srep16529 |
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