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.
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Gordon, S. A., D. Lominadze, J. T. Saari, A. B. Lentsch, and D. A. Schuschke. 2005. Impaired deformability of copper-deficient neutrophils. Exp. Biol. Med. 230:543–548.
Lominadze, D., J. T. Saari, S. S. Percival, and D. A. Schuschke. 2004. Proinflammatory effects of copper deficiency on neutrophils and lung endothelial cells. Immunol. Cell Biol. 82:231–238.
Lentsch, A. B., A. Kato, J. T. Saari, and D. A. Schuschke. 2001. Augmented metalloproteinase activity and acute lung injury in copper deficient rats. Am. J. Physiol. 281:L387–L393.
Schuschke, D. A., S. S. Percival, D. Lominadze, J. T. Saari, and A. B. Lentsch. 2002. Tissue-specific ICAM-1 expression and neutrophil transmigration in the copper-deficient rat. Inflammation. 26:297–303.
Schuschke, D. A., J. T. Saari, and F. N. Miller. 1994. The role of the mast cell in acute inflammatory responses of copper deficient rats. Agents Actions. 42:19–24.
Dalle Lucca, J. J., J. T. Saari, and D. A. Schuschke. 2002. Neointima formation in the rat carotid artery is exacerbated by dietary copper deficiency. Exp. Biol Med. 227:487–491.
Warren, J. S., K. R. Yabroff, D. G. Remick, S. L. Kunkel, S. W. Chensue, R. G. Kunkel, K. J. Johnson, and P. A. Ward. 1989. Tumor necrosis factor participates in the pathogenesis of acute immune complex alveolitis in the rat. J. Clin. Invest. 84:1873–1882.
Azevedo, L. C. P., M. A. Pedro, L. C. Souza, H. P. de Souza, M. Janiszewski, P. L. da Luz, and F. R. M. Laurindo. 2000. Oxidative stress as a signaling mechanism of the vascular response to injury: the redox hypothesis of restenosis. Cardiovasc. Res. 47:436–445.
Morita-Fujimura, Y., M. Fujimura, Y. Gasche, J. C. Copin, and P. H. Chan. 2000. Overexpression of copper and zinc superoxide dismutase in transgenic mice prevents the induction and activation of matrix metalloproteinases after cold injury-induced brain trauma. J. Cereb. Blood Flow Metab. 20:130–138.
O’Donovan, D. A., C. J. Kelly, H. Abdih, D. Bouchier-Hayes, R. W. G. Watson, H. P. Redmond, H. P. Burke, and D. A. Bouchier-Hayes. 1995. Role of nitric oxide in lung injury associated with experimental acute pancreatitis. Br. J. Surg. 82:1122–1126.
Schuschke, D. A., J. C. Falcone, J. T. Saari, J. T. Fleming, S. S. Percival, S. A. Young, J. M. Pass, and F. N. Miller. 2000. Endothelial cell calcium mobilization to acetylcholine is attenuated in copper-deficient rats. Endothelium. 7:83–92.
Falcone, J. C., D. Lominadze, W. T. Johnson, and D. A. Schuschke. 2008. Endothelial cell-derived nitric oxide mobilization is attenuated in copper-deficient rats. Appl. Physiol. Nutr. Metab. 33:1073–1078.
Tomida, T., Y. Numaguchi, Y. Nishimoto, M. Tsuzuki, Y. Hayashi, H. Imai, H. Matsui, and K. Okumura. 2003. Inhibition of COX-2 prevents hypertension and proteinuria associated with a decrease of \({\text{8 - iso - PGF}}_{{2\alpha }} \). Hypertension. 21:601–609.
Lominadze, D., D. A. Schuschke, I. G. Joshua, and W. L. Dean. 2002. Increased ability of erythrocytes to aggregate in spontaneously hypertensive rats. Clin. Exp. Hypertens. 24:397–406.
Morrow, J. D. 2005. Quantification of isoprostanes as indices of oxidant stress and the risk of atherosclerosis in humans. Arterioscler. Thromb. Vasc. Biol. 25:279–286.
Adeagbo, A. S. O., X. Zhang, D. Patel, I. G. Joshua, Y. Wang, X. Sun, I. N. Igbo, and M. A. Oriowo. 2005. Cyclo-oxygenase-2, endothelium and aortic reactivity during deoxycortisone acetate salt-induced hypertension. J. Hypertens. 23:1025–1036.
Kalea, A. Z., D. A. Schuschke, P. D. Harris, and D. J. Klimis-Zacas. 2006. Cyclo-oxygenase inhibition restores the attenuated vasodilation in manganese-deficient rat aorta. J. Nutr. 136:1–6.
Saari, J. T. 2000. Copper deficiency and cardiovascular disease: role of peroxidation, glycation and nitration. Can. J. Physiol. Pharmacol. 78:848–855.
Lynch, S. M., and J. J. Strain. 1989. Effects of copper deficiency on hepatic and cardiac antioxidant enzyme activities in lactose- and sucrose-fed rats. Br. J. Nutr. 61:345–354.
Prohaska, J. R. 1991. Changes in Cu,Zn-superoxide dismutase, cytochrome c oxidase, glutathione peroxidase and glutathione transferase activites in copper-deficient mice and rats. J. Nutr. 121:355–363.
Nelson, S. K., C.-J. Huang, M. M. Mathias, and K. G. D. Allen. 1992. Copper-marginal and copper-deficient diets decrease aortic prostacyclin production and copper-dependent superoxide dismutase activity, and increase aortic lipid peroxidation in rats. J. Nutr. 122:2101–2108.
Sukalski, K. A., T. P. LaBerge, and W. T. Johnson. 1997. In vivo oxidative modification of erythrocyte membrane proteins in copper deficiency. Free Radic. Biol. Med. 22:835–842.
Saari, J. T., F. D. Dickerson, and M. P. Habib. 1990. Ethane production in copper-deficient rats. Proc. Soc. Exp. Biol. Med. 195:30–33.
Rayssiguier, Y., E. Gueux, L. Bussiere, and A. Mazur. 1993. Copper deficiency increases the susceptibility of lipoproteins and tissue to peroxidation in rats. J. Nutr. 123:1343–1348.
Saari, J. T., A. M. Bode, and G. M. Dahlen. 1995. Defects of copper deficiency in rats are modified by dietary treatments that affect glycation. J. Nutr. 125:2925–2934.
Schuschke, D. A., J. T. Saari, and F. N. Miller. 1995. A role for dietary copper in nitric-oxide mediated vasodilation. Microcirculation. 2:371–376.
Kang, Y. J., Z. X. Zhou, H. Wu, G. W. Wang, J. T. Saari, and J. B. Klein. 2000. Metallothionein inhibits myocardial apoptosis in copper-deficient mice: role of atrial natriuretic peptide. Lab Invest. 80:745–757.
Samuelsson, B., R. Morgenstern, and P.-J. Jakobsson. 2007. Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol. Rev. 59:207–224.
Adeagbo, A. S. O., D. Patel, A. Iddrissu, J. Walker, I. G. Joshua, D. A. Schuschke, and Y. Wang. 2003. NS-398, a selective cyclooygenase-2 blocker, acutely inhibits receptor-mediated contractions of rat aorta: role of endothelium. Eur. J. Pharmacol. 458:145–154.
Henrion, D., E. Dechaux, F. J. Dowell, J. Maclour, J.-L. Samuel, B. I. Lévy, and J.-B. Michel. 1997. Alteration of flow-induced dilatation in mesenteric resistance arteries of L-NAME treated rats and its partial association with induction of cyclo-oxygenase-2. Br. J. Pharmacol. 121:83–90.
Lynch, S. M., B. Frei, J. D. Morrow, L. J. Roberts, A. Xu, T. Jackson, R. Reyna, L. M. Klevay, J. A. Vita, and J. F. Keaney. 1997. Vascular superoxide dismutase deficiency impairs endothelial vasodilator function through direct inactivation of nitric oxide and increased lipid peroxidation. Arterioscler. Thromb. Vasc. Biol. 17:2975–2981.
Fang, X., S. A. Moore, J. O. Nwankwo, N. L. Weintraub, L. W. Oberley, G. D. Snyder, and A. A. Spector. 2000. Induction of cyclooxygenase-2 by overexpression of the human catalase gene in cerebral microvascular endothelial cells. J. Neurochem. 75:614–623.
Yang, T., A. Zhang, M. Honeggar, D. E. Kohan, D. Mizel, K. Sanders, J. R. Hoidal, J. P. Briggs, and J. B. Schnermann. 2005. Hypertonic induction of COX-2 in collecting duct cells by reactive oxygen species of mitochondrial origin. J. Biol. Chem. 280:34966–34973.
Acknowledgements
We thank Sharon Gordon for her expert technical assistance. This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-55030. The US Department of Agriculture, Agricultural Research Service, Northern Plains Area, is an equal opportunity/affirmative action employer, and all agency services are available without discrimination.
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Schuschke, D.A., Adeagbo, A.S.O., Patibandla, P.K. et al. Cyclooxygenase-2 is Upregulated in Copper-Deficient Rats. Inflammation 32, 333–339 (2009). https://doi.org/10.1007/s10753-009-9140-4
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DOI: https://doi.org/10.1007/s10753-009-9140-4