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 1␣ , metabolites of TXA 2 and PGI 2 , respectively, were elevated in patients with atherosclerosis compared with normal subjects (3211Ϯ533 versus 679Ϯ63 pg/mg creatinine, PϽ0.001; 594Ϯ156 versus 130Ϯ22 pg/mg creatinine, PϽ0.05, respectively), as was the level of the isoprostane 8-iso-PGF 2␣ . Nimesulide reduced 2,3-dinor-6-keto-PGF 1␣ excretion by 46Ϯ5% (378.3Ϯ103 to 167Ϯ37 pg/mg creatinine, PϽ0.01) preoperatively and blunted the increase after surgery. Nimesulide had no significant effect on 11-dehydro-TXB 2 before (2678Ϯ694 to 2110Ϯ282 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 2␣ 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. (Circulation. 2000;102:840-845.)

Vasoactive enzymes and blood flow responses to passive and active exercise in peripheral arterial disease

“…PAD is an inflammatory condition [39] which is known to promote COX 2 activity [40] and the abundance of atherosclerotic lesions in the vasculature has been directly linked to elevated concentrations of the potent vasoconstrictor, thromboxane [41]. We did not find a difference between groups in enzyme levels of thromboxane synthase, COX 1 or COX 2.…”

Effects of low-dose aspirin on blood pressure and endothelial function of treated hypertensive hypercholesterolaemic subjects

“…Since the reduction of vascular inflammation and oxidative stress has been well documented to contribute to the beneficial prognostic effects of statins, 35 aspirin's ability to modulate inflammatory mediators (prostaglandins, reactive oxygen species) 36 may further enhance the anti-inflammatory effects of statins and contribute to improvement of endothelial function. This hypothesis we formulated after we just happened to find that in those with high cholesterol and without statin therapy, there was no change of endothelial function with aspirin.…”

The balloon catheter induces an increase in contralateral carotid artery reactivity to angiotensin II and phenylephrine

“…The prostaglandin generation is enhanced in patients with atherosclerosis and after balloon angioplasty (Braden et al, 1991;Belton et al, 2000).…”

“…COX 1 is constitutively expressed in most tissues and is largely responsible for TXA 2 formation. COX 2 is normally undetectable or is expressed in low amounts (Masferrer et al, 1994) and it is induced in the vascular smooth muscle and inflammatory cells of human atherosclerotic plaque (Schonbeck et al, 1999;Belton et al, 2000). Prostanoids are also related to the adrenergic response in cultured vascular rabbit smooth muscle cells (Nebigil & Malik, 1992), adrenergic-induced constriction of endothelium-denuded rat abdominal aorta (Asbu´n-Bojalil et al, 2002) and carotid artery (Furuhashi et al, 2000).…”