Cyclooxygenase-1 and-2-dependent prostacyclin formation in patients with atherosclerosis

Background-The formation of prostacyclin (PGI(2)), thromboxane (TX) A(2), a nd isoprostanes is markedly enhanced in atherosclerosis. We examined the re lative contribution of cyclooxygenase (COX)-1 and -2 to the generation of t hese eicosanoids in patients with atherosclerosis. Methods and Results-The study population consisted of 42 patients with athe rosclerosis 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 s tudies localized the COX-2 to proliferating vascular smooth muscle cells an d macrophages. Twenty-four patients who did nut previously receive aspirin were randomized to receive either no treatment or nimesulide at 24 hours be fore surgery and then for 3 days. Eighteen patients who were receiving aspi rin were continued on a protocol of either aspirin alone or a combination o f aspirin and nimesulide. Urinary levels of 11-dehydro-TXB2, and 2.3-dinor- 6-keto-PGF(1 alpha), metabolites of TXA(2) and PGI(2), respectively, were e levated in patients with atherosclerosis compared with normal subjects (321 1+/-533 versus 679+/-63 pg/mg creatinine, P<0.001; 594+/-156 versus 130+/-2 2 pg/mg creatinine, P<0.05, respectively), as was the level of the isoprost ane 8-iso-PGF(2 alpha). Nimesulide reduced 2,3-dinor-6-keto-PGF(1 alpha) ex cretion by 46+/-5% (378.3+/-103 to 167+/-37 pg/mg creatinine, P<0.01) preop eratively and blunted the increase after surgery, Nimesulide had no signifi cant effect on 11-dehydro-TXB2 before (2678+/-694 to 2110+/-282 pg/mg creat inine) or after surgery. The levels of both products were lower in patients who were taking aspirin, and no further reduction was seen with the additi on of nimesulide. None of the treatments influenced urinary 8-iso-PGF(2 alp ha) excretion. Conclusions-Both COX-1 and -2 are expressed and contribute to the increase in PGI, in patients with atherosclerosis, whereas TXA(2) is generated by CO X-1.