MCC950在野百合碱诱导大鼠肺动脉高压模型中的治疗作用及其机制研究  

Rapeutic effect of MCC950 on monocrotaline induced rat pulmonary arterial hypertension and mechanism

作　　者：齐先梅 王蕾 张瑞恒 柳婷 刘杰 杨汀 王军 张知非 王辰 Qi Xianmei;Wang Lei;Zhang Ruiheng;Liu Ting;Liu Jie;Yang Ting;Wang Jun;Zhang Zhifei;Wang Chen(Department of Respirology,Capital Medical University,Beijing100069,China;School of Basic Medical Sciences,Capital Medical University,Beijing100069,China;Respiratory and Critical Care Medicine,China-Japan Friendship Hospital,Beijing100029,China;Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing100730,China)

机构地区：[1]首都医科大学呼吸病学系,北京100069 [2]首都医科大学基础医学院,北京100069 [3]北京中日友好医院呼吸与危重症医学科,北京100029 [4]中国医学科学院北京协和医学院,北京100730

出　　处：《首都医科大学学报》2018年第6期871-876,共6页Journal of Capital Medical University

基　　金：国家重点研发计划项目(2016YF1000605);国家自然科学基金青年基金(31200865)~~

摘　　要：目的探讨MCC950是否可缓解野百合碱(monocrotaline,MCT)诱导的大鼠肺动脉高压。方法雄性SD大鼠27只,采用数字表法随机分为对照组、MCT组和MCT+MCC950 3组,MCT+MCC950组于腹腔注射MCT第16天给予MCC950干预,每2d 1次,共7次。至第31天,检测右心室收缩压、右心肥厚指数;观察肺细小动脉结构,计算血管中膜厚度百分比(media thickness,MT%),检测肺组织中NLRP3、白介素-1β(interleukin-1β,IL-1β)和相关分子的mRNA及蛋白表达情况。结果与对照组比较,MCT组RVSP升高显著[(50. 72±3. 65) mm Hg (1 mm Hg=0. 133 k Pa) vs (24. 29±1. 28) mm Hg,P=0. 000],而MCT+MCC950组与MCT组相比显著降低[(34. 19±1. 94) mm Hg vs (50. 72±3. 65) mm Hg,P <0. 01]。对照组右心肥厚指数为0. 29±0. 01,MCT组(0. 61±0. 04)明显较高,差异有统计学意义(P=0. 000),MCT+MCC950组与MCT组相比降低(0. 48±0. 03 vs 0. 61±0. 04,P <0. 01)。与对照组比较,MCT组大鼠各级肺血管MT%均显著增高(P=0. 000),MCT+MCC950组与MCT组相比降低,且差异有统计学意义(P <0. 01)。MCT组大鼠肺组织中NLRP3、IL-1β和相关分子的mRNA及蛋白表达较对照组均上调,而MCT+MCC950组肺组织中NLRP3、IL-1β和相关分子的表达量与MCT组相比均降低。结论 MCC950可能通过抑制NLRP3信号通路明显改善肺血管重塑,延缓肺动脉高压进程,具应用于肺动脉高压治疗的潜在价值。Objective To explore the effect of MCC950,selective inhibitor of NLRP3inflammasome,on the development of pulmonary hypertension.Methods Male Sprague-Dawley rats were divided into3groups:control group,monocrotaline(MCT)group and MCT+MCC950group.The right ventricular systolic pressure(RVSP),the index of right ventricular hypertrophy(RVHI)and lung morphological feature were assessed.The level of NLRP3,IL-1βand other molecular in lung were assessed by Western blotting and RT-PCR.Results The RVSP,RVHI and the remodeling of the small arteries in the MCT group were significantly higher than control group[(50.72±3.65)mmHg(1mmHg=0.133kPa)vs(24.29±1.28)mmHg,P=0.000]and(0.29±0.01vs0.61±0.04,P=0.000);while decreased after using MCC950compared with MCT group[(34.19±1.94)mmHg vs(50.72±3.65)mmHg,P<0.01]and(0.48±0.03vs0.61±0.04,P<0.01).The protein expression level and the transcription of NLRP3,IL-1βand other molecular in lung of MCT group were increased.The administration of MCC950decreased the protein expression level and the transcription of NLRP3,IL-1βand other molecular compared to MCT group.Conclusion MCC950may attenuates pulmonary vascular remodeling and delaying the process of pulmonary hypertension by inhibit NLRP3signaling pathway,which has the potential value of use in the treatment of pulmonary hypertension.

关 键 词：肺动脉高压 MCC950 NLRP3 

分 类 号：R543.2[医药卫生—心血管疾病]