Copper deficiency induced emphysema is associated with focal adhesion kinase inactivation.

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.

• Authors: Shiro Mizuno, Masanori Yasuo, Harm J Bogaard, Donatas Kraskauskas, Aysar Alhussaini, Jose Gomez-Arroyo, Daniela Farkas, Laszlo Farkas, Norbert F Voelkel
• Journal: PloS one (PLoS One) Vol. 7 Issue 1 Pg. e30678 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22276220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1,2,4,5-benzenetetraamine
• Aniline Compounds
• Apoptosis Regulatory Proteins
• Bcl-2-Like Protein 11
• Bcl2l11 protein, rat
• Membrane Proteins
• Proto-Oncogene Proteins
• RNA, Small Interfering
• Copper
• Focal Adhesion Protein-Tyrosine Kinases
• Caspase 3
• Caspase 8

Topics

• Aniline Compounds (toxicity)
• Animals
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Bcl-2-Like Protein 11
• Blotting, Western
• Caspase 3 (genetics, metabolism)
• Caspase 8 (genetics, metabolism)
• Copper (deficiency)
• Emphysema (enzymology, etiology, genetics)
• Focal Adhesion Protein-Tyrosine Kinases (genetics, metabolism)
• Immunohistochemistry
• Immunoprecipitation
• Male
• Membrane Proteins (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA, Small Interfering
• Rats
• Real-Time Polymerase Chain Reaction