Cyclooxygenase-2 is Upregulated in Copper-Deficient Rats
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Cyclooxygenase-2 is Upregulated in Copper-Deficient Rats Dale A. Schuschke,1,4 Ayotunde S. O. Adeagbo,1 Phani K. Patibandla,1 Uchechi Egbuhuzo,1 Rafael Fernandez-Botran,2 and W. Thomas Johnson3
Abstract—Copper deficiency inactivates Cu/Zn-SOD and promotes accumulation of reactive oxygen species. This process likely impairs nitric oxide (NO)-mediated relaxation as well as triggers vascular inflammation. The current study was designed to determine whether COX-2, a proinflammatory protein, expression and activity are upregulated in the oxidative environment associated with inadequate Cu. Weanling male Sprague Dawley rats were fed purified diets which were either Cu-adequate (Cu-A); Cu-marginal (Cu-M), Cu-deficient (Cu-D), or the Cu-D diet combined with the SOD mimetic Tempol (Cu-D/T; 1 mM in drinking water) for 4 weeks. COX-2 protein, PGE2 (COX-2 metabolite) and isoprostanes (index of oxidative stress) were all higher in the Cu-D group vs Cu-A group, but no significant differences occurred between the Cu-M and Cu-A groups. Tempol protected against an attenuation of NO-mediated vasodilation in the Cu-D rats but did not prevent the elevation of PGE2 or isoprostanes. Our data suggest a role for copper as a modulator of oxidative stress and inflammation independent of SOD activity or NO-derived oxidants. KEY WORDS: copper; cyclooxygenase-2; prostaglandin E2; isoprostane; Tempol.
INTRODUCTION
lated by IgG immune complex in rat lungs [3]. Other findings show that the IgG immune complex elicits a significant increase in matrix metalloproteinases MMP-2 and MMP-9 [3] and that the inflammatory response to balloon injury in the rat carotid artery includes a significantly enhanced smooth muscle proliferation and neointimal formation [6] in copper-deficient rats. While the evidence for augmented inflammation during Cu-deficiency is clear, the signaling mechanisms for the augmented responses are not well defined. For instance, the IgG immune complex response is mediated by TNF-α [7] but even though TNF-α was elevated in both Cu-adequate controls and in Cudeficient rats when stimulated by IgG immune complex, but there was no difference in TNF-α concentration between the groups. Macrophage inflammatory protein-2 (MIP-2) is a critical neutrophil chemokine that promotes neutrophil chemoattraction in lungs. However, while neutrophil accumulation in rat lungs is increased during Cu-deficiency [3, 4], there is no increase in MIP-2 [1].
Inadequate dietary intake of copper is known to promote exaggerated inflammatory responses in experimental animal models. For example, Cu-deficiency causes activation of both neutrophils and endothelial cells as evidenced by polymerization of F-actin [1, 2] and neutrophil accumulation within the lung microcirculation [3, 4]. Copper deficiency also significantly increases protein extravasation from post-capillary venules in response to mast cell degranulation [5] or when stimu1
Department of Physiology and Biophysics, Health Sciences Center A1111, University of Louisville School of Medicine, Louisville, KY 40292, USA 2 Departme
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