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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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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. |
format | Online Article Text |
id | pubmed-3262830 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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