Advertisement

Inflammation

, Volume 32, Issue 5, pp 333–339 | Cite as

Cyclooxygenase-2 is Upregulated in Copper-Deficient Rats

  • Dale A. SchuschkeEmail author
  • Ayotunde S. O. Adeagbo
  • Phani K. Patibandla
  • Uchechi Egbuhuzo
  • Rafael Fernandez-Botran
  • W. Thomas Johnson
Article

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 

Notes

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.

References

  1. 1.
    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.Google Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    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.Google Scholar
  4. 4.
    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.PubMedCrossRefGoogle Scholar
  5. 5.
    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.PubMedCrossRefGoogle Scholar
  6. 6.
    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.Google Scholar
  7. 7.
    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.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar
  9. 9.
    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.PubMedCrossRefGoogle Scholar
  10. 10.
    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.PubMedCrossRefGoogle Scholar
  11. 11.
    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.PubMedGoogle Scholar
  12. 12.
    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.PubMedCrossRefGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    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.PubMedCrossRefGoogle Scholar
  16. 16.
    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.PubMedCrossRefGoogle Scholar
  17. 17.
    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.Google Scholar
  18. 18.
    Saari, J. T. 2000. Copper deficiency and cardiovascular disease: role of peroxidation, glycation and nitration. Can. J. Physiol. Pharmacol. 78:848–855.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedCrossRefGoogle Scholar
  20. 20.
    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.PubMedGoogle Scholar
  21. 21.
    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.PubMedGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    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.PubMedGoogle Scholar
  24. 24.
    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.PubMedGoogle Scholar
  25. 25.
    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.PubMedGoogle Scholar
  26. 26.
    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.PubMedCrossRefGoogle Scholar
  27. 27.
    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.PubMedGoogle Scholar
  28. 28.
    Samuelsson, B., R. Morgenstern, and P.-J. Jakobsson. 2007. Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol. Rev. 59:207–224.PubMedCrossRefGoogle Scholar
  29. 29.
    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.PubMedCrossRefGoogle Scholar
  30. 30.
    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.PubMedCrossRefGoogle Scholar
  31. 31.
    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.PubMedGoogle Scholar
  32. 32.
    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.PubMedCrossRefGoogle Scholar
  33. 33.
    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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Dale A. Schuschke
    • 1
    Email author
  • Ayotunde S. O. Adeagbo
    • 1
  • Phani K. Patibandla
    • 1
  • Uchechi Egbuhuzo
    • 1
  • Rafael Fernandez-Botran
    • 2
  • W. Thomas Johnson
    • 3
  1. 1.Department of Physiology and Biophysics, Health Sciences Center A1111University of Louisville School of MedicineLouisvilleUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of Louisville School of MedicineLouisvilleUSA
  3. 3.Grand Forks Human Nutrition Research CenterGrand ForksUSA

Personalised recommendations