mmLDL通过p38 MAPK通路上调小鼠肠系膜动脉ET受体  

Minimally modified low-density lipoprotein up-regulates endothelin receptors in mouse mesenteric artery through p38 MAPK pathway

作　　者：谢希 陈琛 林杰 汤宏霞 秦旭平[2] 李洁 XIE Xi;CHEN Chen;LIN Jie;TANG Hong-xia;QIN Xu-ping;LI Jie(Chenzhou No.1 People’s Hospital,Affiliated Hospital of University of South China,Chenzhou 423000,China;Institute of Pharmacy and Pharmacology,University of South China,Hengyang 421001,China)

机构地区：[1]南华大学附属郴州医院,郴州市第一人民医院,湖南郴州423000 [2]南华大学药物药理研究所,湖南衡阳421001

出　　处：《中国病理生理杂志》2020年第5期779-787,共9页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.81202535);湖南省教育厅创新平台开放基金资助项目(No.19K084);湖南省教育厅一般项目(No.19C1722);湖南省卫生计生委员会资助课题(No.B2017183);湖南省科技厅自然科学基金资助项目(No.2018JJ6097);郴州市脂质代谢紊乱诊疗技术研发中心项目(No.yfzx201907);郴州市科技局资助项目(No.zdyf201821,No.zdyf201925)。

摘　　要：目的:探讨弱氧化修饰低密度脂蛋白(mm LDL)是否通过激活p38 MAPK炎症通路上调小鼠肠系膜动脉内皮素(ET)A型(ETA)和B型(ETB)受体。方法:将昆明小鼠分为正常对照组(尾静脉注射生理盐水)、mm LDL组(尾静脉注射mm LDL)、LDL组(尾静脉注射LDL)、mm LDL+SB 203580组(尾静脉注射mm LDL及腹腔注射p38 MAPK抑制剂SB 203580)和mm LDL+DMSO组(尾静脉注射mm LDL及腹腔注射DMSO)。微血管张力描记仪记录ETB受体激动剂角蝰毒素6c和ET-1引起肠系膜动脉收缩的量效曲线;RT-q PCR检测ETB受体、ETA受体和白细胞介素(IL-6)的m RNA表达;ELISA检测血清IL-6的水平;Western blot检测ETB受体、ETA受体、IL-6、p38 MAPK、p-p38MAPK、NF-κB和p-NF-κB的蛋白水平。结果:mm LDL引起ETB受体和ETA受体介导的血管收缩反应显著增强(P<0.01),ETB受体、ETA受体和IL-6的m RNA和蛋白表达显著增加(P<0.01),p-p38 MAPK和p-NF-κB蛋白水平显著升高(P<0.01),血清中IL-6水平显著升高(P<0.01);腹腔注射SB 203580抑制了mm LDL的作用。mm LDL引起的IL-6血清浓度升高分别与ETB受体和ETA受体介导的最大收缩率呈正相关。结论:mm LDL通过激活p38 MAPK通路及下游NF-κB转录因子,提高炎症因子IL-6血清水平,增加小鼠肠系膜动脉IL-6、ETA受体和ETB受体表达,增强ETA受体和ETB受体介导的血管收缩功能。AIM:To investigate whether minimally modified low-density lipoprotein(mm LDL)affects the quantity and activity of endothelin(ET)type A(ETA)and type B(ETB)receptors in mouse mesenteric artery by activating p38 mitogen-activated protein kinase(MAPK)inflammatory pathway.METHODS:The KM mice were divided into normal saline(NS)group(injection of NS via caudal vein),mm LDL group(injection of mm LDL via caudal vein),LDL group(injection of LDL via caudal vein),mm LDL+SB 203580 group(injection of mm LDL via caudal vein and intraperitoneal injection of p38 MAPK pathway specific inhibitor SB 203580)and mm LDL+DMSO group(injection of mm LDL via caudal vein and intraperitoneal injection of DMSO).Mesenteric artery ring segment vasoconstriction dose-response curves affected by sarafotoxin 6c(S6c)and ET-1 were recorded by the myography system.The m RNA levels of ETBreceptor,ETAreceptor and interleukin-6(IL-6)were detected by RT-q PCR.The protein levels of ETBreceptor,ETAreceptor,IL-6,p38 MAPK,p-p38 MAPK,NF-κB and p-NF-κB were determined by Western blot.The serum concentration of IL-6was measured by ELISA.RESULTS:The contractile responses of the blood vessel segments to S6c and ET-1 were significantly increased by mm LDL(P<0.01).The m RNA and protein expression levels of ETAreceptor,ETBreceptor,and IL-6significantly increased(P<0.01).The protein levels of p-p38 MAPK and p-NF-κB were significantly increased(P<0.01).The serum level of IL-6 was significantly increased(P<0.01).These effects of mm LDL were inhibited by p38MAPK inhibitor SB 203580.CONCLUSION:mm LDL increses the serum concentration of IL-6,up-regulates the expression of IL-6,ETAreceptor and ETBreceptor in mouse mesenteric artery,and enhances the vasoconstriction function mediated by ETAand ETBreceptors,which is related to the activation of p38 MAPK inflammatory pathway and downstream NF-κB pathway.

关 键 词：弱氧化修饰低密度脂蛋白 p38 MAPK信号通路 内皮素受体 白细胞介素6 

分 类 号：R543.5[医药卫生—心血管疾病] R363.2[医药卫生—内科学]