Cyclooxygenase-1 and -2–Dependent Prostacyclin Formation in Patients With Atherosclerosis

Abstract

Background —The formation of prostacyclin (PGI 2 ), thromboxane (TX) A 2 , and isoprostanes is markedly enhanced in atherosclerosis. We examined the relative contribution of cyclooxygenase (COX)-1 and -2 to the generation of these eicosanoids in patients with atherosclerosis. Methods and Results —The study population consisted of 42 patients with atherosclerosis who were undergoing surgical revascularization. COX-2 mRNA was detected in areas of atherosclerosis but not in normal blood vessel walls, and there was evidence of COX-1 induction. The use of immunohistochemical studies localized the COX-2 to proliferating vascular smooth muscle cells and macrophages. Twenty-four patients who did not previously receive aspirin were randomized to receive either no treatment or nimesulide at 24 hours before surgery and then for 3 days. Eighteen patients who were receiving aspirin were continued on a protocol of either aspirin alone or a combination of aspirin and nimesulide. Urinary levels of 11-dehydro-TXB 2 and 2,3-dinor-6-keto-PGF 1α , metabolites of TXA 2 and PGI 2 , respectively, were elevated in patients with atherosclerosis compared with normal subjects (3211±533 versus 679±63 pg/mg creatinine, P <0.001; 594±156 versus 130±22 pg/mg creatinine, P <0.05, respectively), as was the level of the isoprostane 8-iso-PGF 2α . Nimesulide reduced 2,3-dinor-6-keto-PGF 1α excretion by 46±5% (378.3±103 to 167±37 pg/mg creatinine, P <0.01) preoperatively and blunted the increase after surgery. Nimesulide had no significant effect on 11-dehydro-TXB 2 before (2678±694 to 2110±282 pg/mg creatinine) or after surgery. The levels of both products were lower in patients who were taking aspirin, and no further reduction was seen with the addition of nimesulide. None of the treatments influenced urinary 8-iso-PGF 2α excretion. Conclusions —Both COX-1 and -2 are expressed and contribute to the increase in PGI 2 in patients with atherosclerosis, whereas TXA 2 is generated by COX-1.