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Copper Deficiency Induced Emphysema Is Associated with Focal Adhesion Kinase Inactivation

BACKGROUND: Copper is an important regulator of hypoxia inducible factor 1 alpha (HIF-1α) dependent vascular endothelial growth factor (VEGF) expression, and is also required for the activity of lysyl oxidase (LOX) to effect matrix protein cross-linking. Cell detachment from the extracellular matrix...

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Autores principales: Mizuno, Shiro, Yasuo, Masanori, Bogaard, Harm J., Kraskauskas, Donatas, Alhussaini, Aysar, Gomez-Arroyo, Jose, Farkas, Daniela, Farkas, Laszlo, Voelkel, Norbert F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262830/
https://www.ncbi.nlm.nih.gov/pubmed/22276220
http://dx.doi.org/10.1371/journal.pone.0030678
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author Mizuno, Shiro
Yasuo, Masanori
Bogaard, Harm J.
Kraskauskas, Donatas
Alhussaini, Aysar
Gomez-Arroyo, Jose
Farkas, Daniela
Farkas, Laszlo
Voelkel, Norbert F.
author_facet Mizuno, Shiro
Yasuo, Masanori
Bogaard, Harm J.
Kraskauskas, Donatas
Alhussaini, Aysar
Gomez-Arroyo, Jose
Farkas, Daniela
Farkas, Laszlo
Voelkel, Norbert F.
author_sort Mizuno, Shiro
collection PubMed
description BACKGROUND: Copper is an important regulator of hypoxia inducible factor 1 alpha (HIF-1α) dependent vascular endothelial growth factor (VEGF) expression, and is also required for the activity of lysyl oxidase (LOX) to effect matrix protein cross-linking. Cell detachment from the extracellular matrix can induce apoptosis (anoikis) via inactivation of focal adhesion kinase (FAK). METHODOLOGY: To examine the molecular mechanisms whereby copper depletion causes the destruction of the normal alveolar architecture via anoikis, Male Sprague-Dawley rats were fed a copper deficient diet for 6 weeks while being treated with the copper chelator, tetrathiomolybdate. Other groups of rats were treated with the inhibitor of auto-phosphorylation of FAK, 1,2,4,5-benzenetetraamine tetrahydrochloride (1,2,4,5-BT) or FAK small interfering RNA (siRNA). PRINCIPAL FINDINGS: Copper depletion caused emphysematous changes, decreased HIF-1α activity, and downregulated VEGF expression in the rat lungs. Cleaved caspase-3, caspase-8 and Bcl-2 interacting mediator of cell death (Bim) expression was increased, and the phosphorylation of FAK was decreased in copper depleted rat lungs. Administration of 1,2,4,5-BT and FAK siRNA caused emphysematous lung destruction associated with increased expression of cleaved capase-3, caspase-8 and Bim. CONCLUSIONS: These data indicate that copper-dependent mechanisms contribute to the pathogenesis of emphysema, which may be associated with decreased HIF-1α and FAK activity in the lung.
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spelling pubmed-32628302012-01-24 Copper Deficiency Induced Emphysema Is Associated with Focal Adhesion Kinase Inactivation Mizuno, Shiro Yasuo, Masanori Bogaard, Harm J. Kraskauskas, Donatas Alhussaini, Aysar Gomez-Arroyo, Jose Farkas, Daniela Farkas, Laszlo Voelkel, Norbert F. PLoS One Research Article BACKGROUND: Copper is an important regulator of hypoxia inducible factor 1 alpha (HIF-1α) dependent vascular endothelial growth factor (VEGF) expression, and is also required for the activity of lysyl oxidase (LOX) to effect matrix protein cross-linking. Cell detachment from the extracellular matrix can induce apoptosis (anoikis) via inactivation of focal adhesion kinase (FAK). METHODOLOGY: To examine the molecular mechanisms whereby copper depletion causes the destruction of the normal alveolar architecture via anoikis, Male Sprague-Dawley rats were fed a copper deficient diet for 6 weeks while being treated with the copper chelator, tetrathiomolybdate. Other groups of rats were treated with the inhibitor of auto-phosphorylation of FAK, 1,2,4,5-benzenetetraamine tetrahydrochloride (1,2,4,5-BT) or FAK small interfering RNA (siRNA). PRINCIPAL FINDINGS: Copper depletion caused emphysematous changes, decreased HIF-1α activity, and downregulated VEGF expression in the rat lungs. Cleaved caspase-3, caspase-8 and Bcl-2 interacting mediator of cell death (Bim) expression was increased, and the phosphorylation of FAK was decreased in copper depleted rat lungs. Administration of 1,2,4,5-BT and FAK siRNA caused emphysematous lung destruction associated with increased expression of cleaved capase-3, caspase-8 and Bim. CONCLUSIONS: These data indicate that copper-dependent mechanisms contribute to the pathogenesis of emphysema, which may be associated with decreased HIF-1α and FAK activity in the lung. Public Library of Science 2012-01-20 /pmc/articles/PMC3262830/ /pubmed/22276220 http://dx.doi.org/10.1371/journal.pone.0030678 Text en Mizuno et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Mizuno, Shiro
Yasuo, Masanori
Bogaard, Harm J.
Kraskauskas, Donatas
Alhussaini, Aysar
Gomez-Arroyo, Jose
Farkas, Daniela
Farkas, Laszlo
Voelkel, Norbert F.
Copper Deficiency Induced Emphysema Is Associated with Focal Adhesion Kinase Inactivation
title Copper Deficiency Induced Emphysema Is Associated with Focal Adhesion Kinase Inactivation
title_full Copper Deficiency Induced Emphysema Is Associated with Focal Adhesion Kinase Inactivation
title_fullStr Copper Deficiency Induced Emphysema Is Associated with Focal Adhesion Kinase Inactivation
title_full_unstemmed Copper Deficiency Induced Emphysema Is Associated with Focal Adhesion Kinase Inactivation
title_short Copper Deficiency Induced Emphysema Is Associated with Focal Adhesion Kinase Inactivation
title_sort copper deficiency induced emphysema is associated with focal adhesion kinase inactivation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262830/
https://www.ncbi.nlm.nih.gov/pubmed/22276220
http://dx.doi.org/10.1371/journal.pone.0030678
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