Abstract

BackgroundCopper 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).MethodologyTo 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 FindingsCopper 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.ConclusionsThese 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.

Highlights

  • Chronic obstructive pulmonary disease (COPD) and emphysema are large global health problems with a high disease prevalence in smokers and individuals exposed to biomass fuel smoke

  • Administration of 1,2,4,5-BT and focal adhesion kinase (FAK) small interfering RNA (siRNA) caused emphysematous lung destruction associated with increased expression of cleaved capase-3, caspase-8 and Bcl-2 interacting mediator of cell death (Bim). These data indicate that copper-dependent mechanisms contribute to the pathogenesis of emphysema, which may be associated with decreased hypoxia inducible factor 1 alpha (HIF-1a) and FAK activity in the lung

  • We show that copper-deficiency emphysema is associated with impaired expression of hypoxia inducible factor 1 alpha (HIF1a) target genes because of impaired HIF-1a transactivation, and we further show that copper deficiency causes a decreased expression and activity of the focal adhesion kinase (FAK)

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Summary

Introduction

Chronic obstructive pulmonary disease (COPD) and emphysema are large global health problems with a high disease prevalence in smokers and individuals exposed to biomass fuel smoke. Our studies have been inspired both by a human disease model, the X chromosome-linked, Menkes disease, which is characterized by an inherited copper transporter gene mutation and neonatal emphysema [5], and an animal model, the Blotchy mouse, which develops emphysema. Impaired cross linking of matrix protein as a consequence of LOX inhibition provides a rather intuitive explanation for emphysema development in copper-deficient animals, the published data regarding LOX activity dependent emphysema are controversial. Copper is an important regulator of hypoxia inducible factor 1 alpha (HIF-1a) dependent vascular endothelial growth factor (VEGF) expression, and is required for the activity of lysyl oxidase (LOX) to effect matrix protein crosslinking. Cell detachment from the extracellular matrix can induce apoptosis (anoikis) via inactivation of focal adhesion kinase (FAK)

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