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

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.