阿托伐他汀降低急性心肌梗死患者外周血单核细胞环氧化酶2表达并改善早期炎症反应

Atorvastatin reduces the expression of COX-2 mRNA in peripheral blood monocytes in patients with acute myocardial infarction and modulates the early inflammatory response

目的检测急性心肌梗死(AMI)患者外周血单核细胞环氧化酶2(COX-2)MRNA表达及其对白介素6(IL-6)分泌的影响;观察短期阿托伐他汀治疗对AMI患者外周血单核细胞COX-2MRNA表达的影响和意义。方法选取AMI患者40例(AMI组),冠心病(CHD)稳定期患者18例(对照组)。AMI患者被随机分为常规治疗组(N=20)和阿托伐他汀治疗组(常规治疗+阿托伐他汀20MG/D,N=20)治疗一周。抽取对照组及AMI组治疗前后静脉血,分离、纯化单核细胞,培养24H,其中AMI组治疗前的单核细胞培养时,采用不同浓度COX-2特异性抑制剂—塞来昔布干预(浓度分别为0、0·1、1和10ΜMOL/L)。采用逆转录聚合酶链式反应法(RT-PCR)检测单核细胞COX-2MRNA表达,酶联免疫吸附法(ELISA)测定单核细胞培养上清液中IL-6浓度和血浆中高敏CRP浓度。结果AMI组单核细胞COX-2表达(0·92±0·13)明显高于对照组(0·19±0·08)(P<0·05),经阿托伐他汀治疗一周后,其表达降低66%(与常规治疗相比,P<0·05);AMI组单核细胞培养上清液IL-6浓度为(204·8±45·6)NG/L,明显高于对照组(40·9±1·2)NG/L(P<0·05),经不同浓度的塞来昔布(0·01、1和10ΜMOL/L)体外干预培养后,10ΜMOL/L塞来昔布使IL-6浓度下降58%(与基线值相比较,P<0·05),且呈浓度依赖性;AMI组血浆CRP浓度为(43·3±14·9)MG/L,显著高于对照组(1·7±0·8)MG/L,P<0·05,经阿托伐他汀治疗后,CRP水平降低62%(与常规治疗比较,P<0·05);AMI组单核细胞COX-2表达水平与培养上清液中IL-6浓度和血浆中CRP浓度均呈正相关(R=0·636和0·662,均P<0·05)。结论AMI患者外周血单核细胞处于激活状态,单核细胞源性COX-2可能起重要的促炎作用;阿托伐他汀抑制AMI患者外周血单核细胞COX-2表达,并可能通过这一途径改善AMI的早期炎症反应。

Objective To measure the effect of atorvastatin on COX-2 expression in monocytes in patients with acute myocardial infarction （AMI）. Methods Forty patients with AMI （AMI group） and 18 patients with stable coronary heart disease （control group） were enrolled, and patients with AMI were randomly given routine therapy （n = 20） and routine therapy plus atorvastatin （20 mg/day, n = 20 ） for a week. Peripheral blood monocytes for each participant including patients with AMI were isolated and cultured for 24 hours. During the culture, monoctyes in patients with pretreatment AMI were incubated with celecoxib in different concentration （0,0. 1,1 and 10 μmol/L）. COX-2 mRNA expression in monocytes was measured by reverse transcription polymerase chain reaction （RT-PCR） ; concentrations of interleukin-6 （ IL-6 ） in supernatant from monocytes and plasma hs-CRP levels were measured by using enzyme-linked immunosorbent assay （ELISA）. Results COX-2 expression in monocytes in patients with AMI （0. 92 ± 0. 13 ） was significantly higher than that in the control subjects （0. 19±0. 08）, and decreased by 66% after atorvastatin （compared with that on routine therapy, P 〈 0.05） ; IL-6 secretions of monocytes in the AMI group （204. 8 ± 45.6 ng/L） increased dramatically compared with those in the control group （40.9 ± 1.2 ng/L, P 〈0.05）, and reduced dramatically by 58% when incubated with 10 μmol/L celecoxib （P 〈0. 05 ） in a concentrationdependent manner; plasma levels of CRP in the AMI group（43.3 ± 14. 9 mg/L） significantly increased compared with those in the control group （1.7 ± 0.8 mg/L）, and reduced by 62% after atorvastatin （ compared with those in the routine therapy group, P 〈 0. 05 ）. COX-2 expression in monocytes in the AMI group was positively correlated with both secretions of IL-6 and plasma level of CRP （r = 0. 636 and 0. 662, respectively, both P 〈 0. 05 ）. Conclusions There is an inflammatory activation in peripheral blood monocytes in patients with early AMI, and the monocytes-derived COX-2 may play an important role in promoting early inflammatory process. Atorvastatin may decrease COX-2 expression in peripheral blood monocytes in patients with AMI and cyclooxygenase-dependent pathway might be correlated with the antiinflammation mechanism of statin.