Copper Deficiency Induced Emphysema Is Associated with Focal Adhesion Kinase Inactivation

Authors

Shiro Mizuno, Virginia Commonwealth University
Masanori Yasuo, Virginia Commonwealth University
Harm J. Bogaard, VU University Medical Center
Donatas Kraskauskas, Virginia Commonwealth UniversityFollow
Aysar A. Alhussini, Virginia Commonwealth University
Jose Gomez-Arroyo, Virginia Commonwealth University
Daniela Farkas, Virginia Commonwealth University
Laszlo Farkas, Virginia Commonwealth UniversityFollow
Norbert F. Voelkel, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2012

Journal/Book/Conference Title

PLOS ONE

Volume

7

DOI of Original Publication

10.1371/journal.pone.0030678

Comments

Originally Published at http://dx.doi.org/10.1371/journal.pone.0030678

Date of Submission

November 2014

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.

Rights

Copyright: © 2012 Mizuno et al. 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 credited.

Is Part Of

VCU Internal Medicine Publications