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Asef controls vascular endothelial permeability and barrier recovery in the lung

Increased levels of hepatocyte growth factor (HGF) in injured lungs may reflect a compensatory response to diminish acute lung injury (ALI). HGF-induced activation of Rac1 GTPase stimulates endothelial barrier protective mechanisms. This study tested the involvement of Rac-specific guanine nucleotid...

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Autores principales: Tian, Xinyong, Tian, Yufeng, Gawlak, Grzegorz, Meng, Fanyong, Kawasaki, Yoshihiro, Akiyama, Tetsu, Birukova, Anna A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325835/
https://www.ncbi.nlm.nih.gov/pubmed/25518936
http://dx.doi.org/10.1091/mbc.E14-02-0725
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author Tian, Xinyong
Tian, Yufeng
Gawlak, Grzegorz
Meng, Fanyong
Kawasaki, Yoshihiro
Akiyama, Tetsu
Birukova, Anna A.
author_facet Tian, Xinyong
Tian, Yufeng
Gawlak, Grzegorz
Meng, Fanyong
Kawasaki, Yoshihiro
Akiyama, Tetsu
Birukova, Anna A.
author_sort Tian, Xinyong
collection PubMed
description Increased levels of hepatocyte growth factor (HGF) in injured lungs may reflect a compensatory response to diminish acute lung injury (ALI). HGF-induced activation of Rac1 GTPase stimulates endothelial barrier protective mechanisms. This study tested the involvement of Rac-specific guanine nucleotide exchange factor Asef in HGF-induced endothelial cell (EC) cytoskeletal dynamics and barrier protection in vitro and in a two-hit model of ALI. HGF induced membrane translocation of Asef and stimulated Asef Rac1-specific nucleotide exchange activity. Expression of constitutively activated Asef mutant mimicked HGF-induced peripheral actin cytoskeleton enhancement. In contrast, siRNA-induced Asef knockdown or expression of dominant-negative Asef attenuated HGF-induced Rac1 activation evaluated by Rac-GTP pull down and FRET assay with Rac1 biosensor. Molecular inhibition of Asef attenuated HGF-induced peripheral accumulation of cortactin, formation of lamellipodia-like structures, and enhancement of VE-cadherin adherens junctions and compromised HGF-protective effect against thrombin-induced RhoA GTPase activation, Rho-dependent cytoskeleton remodeling, and EC permeability. Intravenous HGF injection attenuated lung inflammation and vascular leak in the two-hit model of ALI induced by excessive mechanical ventilation and thrombin signaling peptide TRAP6. This effect was lost in Asef(−/−) mice. This study shows for the first time the role of Asef in HGF-mediated protection against endothelial hyperpermeability and lung injury.
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spelling pubmed-43258352015-04-30 Asef controls vascular endothelial permeability and barrier recovery in the lung Tian, Xinyong Tian, Yufeng Gawlak, Grzegorz Meng, Fanyong Kawasaki, Yoshihiro Akiyama, Tetsu Birukova, Anna A. Mol Biol Cell Articles Increased levels of hepatocyte growth factor (HGF) in injured lungs may reflect a compensatory response to diminish acute lung injury (ALI). HGF-induced activation of Rac1 GTPase stimulates endothelial barrier protective mechanisms. This study tested the involvement of Rac-specific guanine nucleotide exchange factor Asef in HGF-induced endothelial cell (EC) cytoskeletal dynamics and barrier protection in vitro and in a two-hit model of ALI. HGF induced membrane translocation of Asef and stimulated Asef Rac1-specific nucleotide exchange activity. Expression of constitutively activated Asef mutant mimicked HGF-induced peripheral actin cytoskeleton enhancement. In contrast, siRNA-induced Asef knockdown or expression of dominant-negative Asef attenuated HGF-induced Rac1 activation evaluated by Rac-GTP pull down and FRET assay with Rac1 biosensor. Molecular inhibition of Asef attenuated HGF-induced peripheral accumulation of cortactin, formation of lamellipodia-like structures, and enhancement of VE-cadherin adherens junctions and compromised HGF-protective effect against thrombin-induced RhoA GTPase activation, Rho-dependent cytoskeleton remodeling, and EC permeability. Intravenous HGF injection attenuated lung inflammation and vascular leak in the two-hit model of ALI induced by excessive mechanical ventilation and thrombin signaling peptide TRAP6. This effect was lost in Asef(−/−) mice. This study shows for the first time the role of Asef in HGF-mediated protection against endothelial hyperpermeability and lung injury. The American Society for Cell Biology 2015-02-15 /pmc/articles/PMC4325835/ /pubmed/25518936 http://dx.doi.org/10.1091/mbc.E14-02-0725 Text en © 2015 Tian et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Tian, Xinyong
Tian, Yufeng
Gawlak, Grzegorz
Meng, Fanyong
Kawasaki, Yoshihiro
Akiyama, Tetsu
Birukova, Anna A.
Asef controls vascular endothelial permeability and barrier recovery in the lung
title Asef controls vascular endothelial permeability and barrier recovery in the lung
title_full Asef controls vascular endothelial permeability and barrier recovery in the lung
title_fullStr Asef controls vascular endothelial permeability and barrier recovery in the lung
title_full_unstemmed Asef controls vascular endothelial permeability and barrier recovery in the lung
title_short Asef controls vascular endothelial permeability and barrier recovery in the lung
title_sort asef controls vascular endothelial permeability and barrier recovery in the lung
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325835/
https://www.ncbi.nlm.nih.gov/pubmed/25518936
http://dx.doi.org/10.1091/mbc.E14-02-0725
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