NF-κB-iNOS/COX-2信号通路在高糖损伤血管内皮依赖性舒张中的作用  

Activation of NF-κB-iNOS/COX-2 signaling pathways is involved in impaired endothelium-dependent relaxation under high glucose condition

作　　者：阳创 薛莱 吴阳 邱红梅[1] 蒋青松[1] YANG Chuang;XUE Lai;WU Yang;QIU Hong-mei;JIANG Qing-song(Department of Pharmacology,Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology,Chongqing Medical University,Chongqing 400016,China;Department of Clinical Medicine,Jiangyou People's Hospital,Jiangyou 621700,China;Cardiovascular Center,The Seventh Affiliated Hospital of Sun Yat-sen University,Shenzhen 518107,China)

机构地区：[1]重庆医科大学药学院药理教研室,重庆市生物化学与分子药理学重点实验室,重庆400016 [2]江油市人民医院临床医学部,四川江油621700 [3]中山大学附属第七医院心血管中心,广东深圳518107

出　　处：《中国病理生理杂志》2020年第12期2159-2165,共7页Chinese Journal of Pathophysiology

基　　金：重庆市自然科学基金资助项目(No.cstc2017jcyjAX0211)。

摘　　要：目的:探讨核因子κB(NF-κB)-诱导型一氧化氮合酶(iNOS)/环氧合酶2(COX-2)信号通路在高糖损伤血管内皮依赖性舒张中的作用。方法:采用高糖(55 mmol/L葡萄糖)孵育大鼠胸主动脉环,分别给予NF-κB抑制剂PDTC、iNOS抑制剂SMT和COX-2抑制剂美洛昔康,以累积浓度法观察乙酰胆碱(ACh)对苯肾上腺素预收缩血管的内皮依赖性舒张效应,计算并比较其最大舒张效应(Emax)和产生50%Emax浓度的负对数(pD2)的变化。HE染色和电镜观察血管形态;RT-qPCR和Western blot法分别检测NF-κB、iNOS和COX-2的mRNA和蛋白表达。结果:高糖损伤血管内皮结构完整性;ACh诱导的内皮依赖性舒张明显减弱,Emax和pD2均显著降低(P<0.01);同时,NF-κB、iNOS和COX-2的mRNA和蛋白水平显著升高(P<0.01)。PDTC、SMT和美洛昔康均明显增强高糖损伤的内皮依赖性舒张作用,其Emax和pD2均显著升高(P<0.01)。PDTC除了改善高糖损伤血管内皮结构完整性,也下调高糖升高的NF-κB、iNOS和COX-2的mRNA和蛋白表达(P<0.01)。结论:NF-κB-iNOS/COX-2信号通路激活参与了高糖损伤血管内皮依赖性舒张的作用。AIM:To investigate the role of nuclear factor-κB(NF-κB)-inducible nitric oxide synthase(iNOS)/cyclooxygenase-2(COX-2)signaling pathways in impaired endothelium-dependent relaxation under high glucose(HG)condition.METHODS:The endothelium-dependent relaxation induced by acetylcholine(ACh)in phenylephrineprecontracted rat thoracic aortic ring was performed in the absence or presence of different inhibitors under HG(55 mmol/L glucose)condition,and then the maximal relaxation effect of ACh(Emax)and the negative logarithm of ACh concentration for inducing 50%of Emax(pD2)were calculated.The structure of aorta was observed by HE staining and electron microscopy.The mRNA and protein expression was detected by RT-qPCR and Western blot,respectively.RESULTS:The structure of endothelial cells was interrupted by HG.Meanwhile,ACh-induced vasodilatation was also impaired,in which the Emax and pD2 were both decreased significantly(P<0.01),accompanied by the up-regulation of NF-κB p65,iNOS and COX-2 expression at mRNA and protein levels(P<0.01).The NF-κB inhibitor PDTC,iNOS inhibitor SMT,and COX-2 inhibitor meloxicam restored the ACh-induced vasodilatation under HG condition,in which the Emax and pD2 were increased significantly(P<0.01).Moreover,PDTC attenuated the pathological damage of endothelial structure,and downregulated the expression levels of NF-κB p65,iNOS and COX-2 induced by HG(P<0.01).CONCLUSION:The activation of NF-κB-iNOS/COX-2 signaling pathways is involved in the impaired endothelium-dependent relaxation under HG condition.

关 键 词：核因子ΚB 诱导型一氧化氮合酶 环氧合酶2 高糖 血管内皮依赖性舒张 

分 类 号：R587.1[医药卫生—内分泌] R363.2[医药卫生—内科学]