Investigations on the Significance of Inductable Cyclooxygenase in Atherogenesis in Cholesterol-Fed Rabbits

Marion Wurr, Ingo Nolte, Dirk Stichtenoth

Clinic for Small Animal Surgery, Foundation of Veterinary University, Hannover, Germany.
Clinic for Small Animal Surgery, Foundation of Veterinary University, Hannover, Germany;.
Institute of Clinical Pharmacology, Medical University in Hannover, Hannover, Germany..

DOI: 10.4236/pp.2012.32032                

Abstract

Atherosclerosis is the most prevalent disease in middle and later years of human life. Heart attacks and strokes are among the most frequent causes of death. New approaches in therapy are the use of NSAID’s (nonsteroidal antiphlogistical drugs) of the new generation (selective inhibitors of COX-2) and DHEA (Dehydroepiandrostenon). The key enzyme of prostaglandin synthesis, the COX-2 isoenzyme, is predominantly found in inflammatory tissue. Out of this results a possible importance of COX-2-inhibitors in prophylaxis of atherosclerosis. Our study intended to examine the significance of COX-2 and the COX-2-formed prostanoids, as well as the significance of COX-2-independent iso-prostanes on atherosclerosis. For that purpose we tested the effect of the selective COX-2-inhibitor Celecoxib on rabbits fed with cholesterol and compared this with the effect of the steroid hormone DHEA in 4 groups: healthy control, cholesterol-fed control, DHEA-group and Celecoxib group. In the test prostanoids, nitrate and nitrite were measured by gas chromatograpy/tandem-mass-spectrometry (GC-MS/MS) in 24-hours-collected urine. Additionally we measured cholesterol and triglycerides in plasma. The aortas of the examinated animals were measured optically using a planimetrical method. The measurement of prostanoids, isoprostanes, nitrate and nitrite showed considerable variations and particulary significant differences (p < 0.01) even in the initial values. By the treatment with Celecoxib the rate of atherosclerosis was reduced in a highly significant way in comparison to the cholesterol group and the DHEA-group. Consequently the test demonstrated a significant role of COX-2 in the development of atherogenesis.

Keywords

Celecoxib; DHEA; Plaques; Prostanoide

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	R. A. Cohen, K. M. Zitnay, C. C. Haudenschild and L. D. Cunningham, “Loss of Selective Endothelial Cell Vasoactive Functions Caused by Hypercholesterinemia in Pig Coronary Arteries,” Circulation Research, Vol. 63, No. 5, 1988, pp. 903-910.
[2]	E. Barret-Connor and K. T. Khaw, “A Prospective Study of Dehydroepiandrosterone Sulfate Mortality and Cardiovascular Disease,” New England Journal of Medicine, Vol. 315, No. 24, 1986, pp. 1519-1524.
[3]	E. E. Baulieu, “Dehydroepiandrosterone (DHEA): A Fountain of Youth?” Journal of Clinical Endocrinology & Metabolism, Vol. 81, 1996, pp. 3147-3151. doi:10.1210/jc.81.9.3147
[4]	A. J. Moralea, J. J. Nolan and J. C. Nelson, “YEN Ssc. Effects of Replacement Dose of Dehydroepiandrosterone in Men and Women of Advancing Age,” Journal of Clinical Endocrinology & Metabolism, Vol. 78, 1994, pp. 1360-1367. doi:10.1210/jc.78.6.1360
[5]	K. T. Khaw, “Dehydroepiandrosterone, Dehydroepiandrosterone Sulphate and Cardiovascular Disease,” Journal of Endodontics, Vol. 150, 1996, pp. S149-S153.
[6]	J. K. Gierse, S. D. Hauser, D. P. Creely, C. Koboldt, S. H. Rangwala, P. C. Isakson and K. Seibert, “Expression and Selective Inhibition of the Constitutive and Inducible Forms of Human Cyclooxygenase,” Biochemical Journal, Vol. 305, 1995, pp. 479-484.
[7]	G. B. Gordon, D. Bush, H. F. Weisman, “Reduction of Artherosclerosis by Administration of Dehydroepiandrosterone,” Journal of Clinical Investigation, Vol. 82, No. 2, 1988, pp. 712-720. doi:10.1172/JCI113652
[8]	D. M. Herrington, “Dehydroepiandrosterone and Coronary Atherosclerosis,” Annals of the New York Academy of Sciences, Vol. 774, 1995, pp. 271-280. doi:10.1111/j.1749-6632.1995.tb17387.x-i1
[9]	P. T. Leese, R. C. Hubbard, A. Karim, P. C. Isakson, S. S. Yu and G. S. Geis, “Effects of Celecoxib, a Novel Cyclooxgenase-2-Inhibitor, on Platelet Function in Healthy Adults: A Randomised, Controlled Trial,” Journal of Clinical Pharmacology, Vol. 40, No. 2, 2000, pp. 124-132. doi:10.1177/00912700022008766
[10]	J. C. Fr?lich, “Selektive Cyclooxygenasehemmer-Eine neue Generation von Antirheumatika,” Deutsches ?rzte- blatt, Vol. 47, No. 23, 1996, pp. 3100-3101.
[11]	P. E. Lipsky and P. C. Isakson, “Outcome of Specific COX Inhibition in Rheumatoid Arthritis,” Journal of Rheumatology, Vol. 24, Suppl. 49, 1997, pp. 9-14.
[12]	K. Seibert, Y. Zhang, K. Leahy, S. Hauser, J. Masferrer, W. Perkins, L. Lee and P. Isakson, “Pharmacological and Biochemical Demonstration of the Role of Cyclooxygenase 2 in Inflammation and Pain,” Proceedings of the National Academy of Sciences USA, Vol. 91, 1994, pp. 12013-12017
[13]	J. C. Fr?lich, “A Classification of NSAID’s According to the Relative Inhibition of Cyclooxygenase Isoenzymes,” Journal of Pharmacological Sciences, Vol. 18, 1997, pp. 1-35.
[14]	J. C. Fr?lich, “Prostaglandin Endoperoxide Syntherase Isoenzymes: The Clinical Relevance of Selective Inhibi- tion,” Annals of the Rheumatic Diseases, Vol. 82, 1995, pp. 712-720.
[15]	J. C. Fr?lich and D. O. Stichtenoth, “Renal Side Effects of NSAID’s: Role of COX-1 and COX-2,” Selective Cox-2 Inhibitors: Pharmacology, Clinical Effects and Therapeutical Potential, Springer, Berlin, 1998, pp. 87- 97.
[16]	D. O. Stichtenoth, H. Zeidler and J. C. Fr?lich, “Neue Nichtsteroidale Antirheumatika: Selektive Hemmstoffe der Induzierbaren Cyclooxygenase,” Medizinische Klinik Vol. 93, 1998, pp. 407-415.
[17]	D. O. Stichtenoth and J. C. Fr?lich, “COX-2 and the Kidneys,” Current Pharmaceutical Design, Vol. 6, No. 17, 2000, pp. 1737-1753.
[18]	D. O. Stichtenoth and J. C. Fr?lich, “Therapie Mit Pr?ferentiellen und Spezifischen COX-2-Inhibitoren,” Internist, Vol. 42, 2001, pp. 421-426.
[19]	R. C. Hubbard, D. L. Mehlisch, D. R. Jasper, M. J. Nugent, S. Yu and P. C. Isakson, “SC-58625, a Highly Selective Inhibitor of COX-2, Is an Effective Analgesic in an Acute Post-Surgial Pain Model,” Journal of Investigative Medicine, Vol. 44, 1996, p. 293A
[20]	R. Jouve, I. Juhan-Vague, M. Aillaud, M. Serment-Jouve and H. Payan, “Comparison of the Effects of Aspirin and Indomethacin on Aortic Artherogenesis Induced in Rabbits,” Artherosclerosis, Vol. 42, 1982, pp. 319-321. doi:10.1016/0021-9150(82)90159-9
[21]	L. S. Simon, A. Weaver, D. Y. Graham, et al., “Anti-Inflammatory and Upper Gastrointestinal Effects of Celecoxib in Rheumatoid Arthritis,” JAMA, Vol. 282, No. 20, 1999, pp. 1921-1928. doi:10.1001/jama.282.20.1921
[22]	D. O. Stichtenoth and J. C. Fr?lich, “The Second Genera- tion of COX-2-Inhibitors,” Drugs, Vol. 63, No. 1, 2003, pp. 33-45. doi:10.2165/00003495-200363010-00003
[23]	J. D. Morrow and L. J. Roberts II, “The Isoprostanes: Unique Bioactive Products of Lipid Peroxidation,” Progress in Lipid Researc, Vol. 36, No. 1, 1997, pp. 1-21. doi:10.1016/S0163-7827(97)00001-5
[24]	J. D. Morrow and L. J. Roberts II, “The Isoprostanes, Current Knowledge and Directions for Future Research,” Biochemical Pharmacology, Vol. 51, No. 1, 1996, pp. 1-9. doi:10.1016/0006-2952(95)02072-1
[25]	S. M. Bode-B?ger, R. H. B?ger, S. Kienke, M. B?hme, L. Phivtongngam, D. Tsikas and J. C. Fr?lich, “Chronic Dietary Supplementation with L-Arginine Inhibits Platelet Aggregation and Thromboxane A2 Synthesis in Hypercholesteraemic Rabbits in Vivo,” Cardivascular Research, Vol. 37, 1998, pp. 756-764. doi:10.1016/S0008-6363(97)00295-2
[26]	N. Delanty, M. Reilly, D. Practico, J. A. Lawson, J. F. Mc Carthy, “8-epi PGF2-Generation during Coronary Reperfusion,” Circulation, Vol. 95, 1997, pp. 2492-2499.
[27]	D. O. Stichtenoth and J. C. Fr?lich, “COX-2 and the Kidneys,” Current Pharmaceutical Design, Vol. 6, No. 17, 2000, pp. 1737-1753.
[28]	D. Tsikas, F.-M. Gutzki, M. B?hme, I. Fuchs and J. C. Fr?lich, “Solid- and Liquid-Phase Extraction for the Gas Chromatographic-Tandem Mass Spectrometric Quantification of 2,3-Dinor-thromboxane B2 and 2,3-Dinor-6-oxo-prostaglandin F1α in Human Urine,” Journal of Chromatography A, Vol. 885, 2000, pp. 351-359. doi:10.1016/S0021-9673(99)00967-X
[29]	D. Tsikas, “Silmultaneus Derivazation and Quantification of the Nitric Oxide Metabolites Nitrite and Nitrate in Biological Fluids by Gas Chromatography/Mass Spectrometry,” Analytical Chemistry, Vol. 72, No. 17, 2000, pp. 4064-4072. doi:10.1021/ac9913255
[30]	D. Practicó, L. Iuliano, L. Spagnioli, J. Maclouf, F. Violi, G. A. FitzGerald, “Monocytes in Human Artherosclerotic Plaque Contain Levels of 8-epi PGF2. An Index of Oxidative Stress in Vivo,” Circulation, Vol. 94, 1996, p. 1611.
[31]	L. J. Roberts II and J. D. Morrow, “The Generation and Actions of Isoprostanes,” Biochimica et Biophysica Acta, Vol. 1345, No. 2, 1997, pp. 121-135.
[32]	E. Schwedhelm, D. Tsikas, T. Durand, F.-M. Gutzki, A. Guy, J.-C. Rossi and J. C. Fr?lich, “Tandem Mass Spectrometric Quantification of 8-Iso-Prostaglandin F2α and Its Metabolite 2,3-Dinor-8-iso-prostaglandin F2α in Human Urine,” Journal of Chromatography B, Vol. 744, 2000, pp. 9-112.
[33]	D. Tsikas, E. Schwedhelm, J. Fauler, F.-M. Gutzki, E. Mayatepek and J. C. Fr?lich, “Specific and Rapid Quantification of 8-Iso-Prostaglandin F2α in Urine of Healthy Humans and Patients with Zellweger Syndrome by Gas Chromatography-Tandem Mass Spectrometry,” Journal of Chromatography B, Vol. 716, 1998, pp. 7-17. doi:10.1016/S0378-4347(98)00275-8