动脉粥样硬化患者中环氧合酶-1和-2依赖性前列环素的形成

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

作者信息

Belton O, Byrne D, Kearney D, Leahy A, Fitzgerald D J

机构信息

Department of Clinical Pharmacology and Surgery, Royal College of Surgeons in Ireland, St Stephens Green, Dublin, Ireland.

出版信息

Circulation. 2000 Aug 22;102(8):840-5. doi: 10.1161/01.cir.102.8.840.

DOI:10.1161/01.cir.102.8.840

PMID:10952950

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(1alpha), 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(2alpha). Nimesulide reduced 2, 3-dinor-6-keto-PGF(1alpha) 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(2alpha) 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.

摘要

背景

在动脉粥样硬化中，前列环素（PGI₂）、血栓素（TX）A₂和异前列腺素的生成显著增强。我们研究了环氧化酶（COX）-1和-2在动脉粥样硬化患者中这些类花生酸生成中的相对作用。

方法与结果

研究人群包括42例接受外科血管重建术的动脉粥样硬化患者。在动脉粥样硬化区域检测到COX-2 mRNA，但在正常血管壁中未检测到，且有COX-1诱导的证据。免疫组织化学研究表明COX-2定位于增殖的血管平滑肌细胞和巨噬细胞。24例此前未服用阿司匹林的患者被随机分为两组，一组在手术前24小时不接受任何治疗，另一组接受尼美舒利治疗，术后再持续治疗3天。18例正在服用阿司匹林的患者继续接受单独使用阿司匹林或阿司匹林与尼美舒利联合使用的方案。与正常受试者相比，动脉粥样硬化患者尿液中TX A₂的代谢产物11-脱氢-TXB₂和PGI₂的代谢产物2,3-二去甲-6-酮-PGF₁α水平升高（分别为3211±533与679±63 pg/mg肌酐，P<0.001；594±156与130±22 pg/mg肌酐，P<0.05），异前列腺素8-异-PGF₂α水平也升高。尼美舒利术前使2,3-二去甲-6-酮-PGF₁α排泄减少46±5%（从378.3±103降至167±37 pg/mg肌酐，P<0.01），并减弱了术后的升高。尼美舒利对术前（从2678±694降至2110±282 pg/mg肌酐）和术后的11-脱氢-TXB₂均无显著影响。服用阿司匹林患者的两种产物水平均较低，加用尼美舒利后未见进一步降低。所有治疗均未影响尿液中8-异-PGF₂α的排泄。