Copper Deficiency Induced Emphysema is Associated with Focal Adhesion Kinase Inactivation

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Jan 26

PMID 22276220

Citations 15

Authors

Shiro Mizuno

Masanori Yasuo

Harm J Bogaard

Donatas Kraskauskas

Aysar Alhussaini

Jose Gomez-Arroyo

Daniela Farkas

Laszlo Farkas

Norbert F Voelkel

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Copper homeostasis dysregulation in respiratory diseases: a review of current knowledge.

Song W, Yue Y, Zhang Q, Wang X Front Physiol. 2024; 15:1243629.

PMID: 38883186 PMC: 11176810. DOI: 10.3389/fphys.2024.1243629.

Characterization of the COPD alveolar niche using single-cell RNA sequencing.

Sauler M, McDonough J, Adams T, Kothapalli N, Barnthaler T, Werder R Nat Commun. 2022; 13(1):494.

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Systemic Copper Disorders Influence the Olfactory Function in Adult Rats: Roles of Altered Adult Neurogenesis and Neurochemical Imbalance.

Adamson S, Zheng W, Agim Z, Du S, Fleming S, Shannahan J Biomolecules. 2021; 11(9).

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Imbalance Between Injury and Defense in the COPD Emphysematous Phenotype.

Bai S, Zhao L Front Med (Lausanne). 2021; 8:653332.

PMID: 34026786 PMC: 8131650. DOI: 10.3389/fmed.2021.653332.

Nutritional immunity: the impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease.

Healy C, Munoz-Wolf N, Strydom J, Faherty L, Williams N, Kenny S Respir Res. 2021; 22(1):133.

PMID: 33926483 PMC: 8082489. DOI: 10.1186/s12931-021-01722-y.

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