title: 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).
  
  
  METHODS
  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).
  
  
  RESULTS
  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.affiliation: Pulmonary and Critical Care Medicine Division and Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Shiro
authors.initials: S
authors.lastname: Mizuno
authors.forename: Masanori
authors.initials: M
authors.lastname: Yasuo
authors.forename: Harm J
authors.initials: HJ
authors.lastname: Bogaard
authors.forename: Donatas
authors.initials: D
authors.lastname: Kraskauskas
authors.forename: Aysar
authors.initials: A
authors.lastname: Alhussaini
authors.forename: Jose
authors.initials: J
authors.lastname: Gomez-Arroyo
authors.forename: Daniela
authors.initials: D
authors.lastname: Farkas
authors.forename: Laszlo
authors.initials: L
authors.lastname: Farkas
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
mesh_terms: D000814:Aniline Compounds / Q000633:toxicity; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D003300:Copper / Q000172:deficiency*; D004646:Emphysema / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C539551:1,2,4,5-benzenetetraamine; D000814:Aniline Compounds; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D003300:Copper; D051416:Focal Adhesion Protein-Tyrosine Kinases; D053148:Caspase 3; D053181:Caspase 8