神经母细胞瘤抑瘤蛋白1在肺动脉高压大鼠中的表达变化  

Expression change of NBL1 in rats with pulmonary arterial hypertension

作　　者：孟刘坤[1] 滕晓[1] 袁雯 孟健[1] 李君[1] 刘晓艳[2] MENG Liu-kun;TENG Xiao;YUAN Wen;MENG Jian;LI Jun;LIU Xiao-yan(State Key Lab of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037,China;Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China)

机构地区：[1]中国医学科学院北京协和医学院国家心血管病中心阜外医院心血管疾病国家重点实验室,北京100037 [2]首都医科大学附属北京朝阳医院医学研究中心,北京100020

出　　处：《中国药理学通报》2019年第9期1226-1231,共6页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金青年基金(No 81400034,81500038);北京市自然科学基金面上项目(No 7172182,7172078);北京朝阳医院1351人才培养计划(No CYXX-2017-36)

摘　　要：目的 研究神经母细胞瘤抑瘤蛋白1(neuroblastoma suppression of tumorigenicity 1,NBL1)在野百合碱(monocro-taline,MCT)诱导的肺动脉高压(pulmonary arterial hyperten-sion,PAH)大鼠中表达的变化.方法 将40只大鼠随机分为对照组(n=10)和MCT组(n=30).MCT组腹腔注射MCT 60 mg·kg-1,对照组腹腔注射等体积生理盐水;3周、4周、5周后,检测肺组织和血浆中NBL1的变化.结果 MCT注射后3周、4周、5周,大鼠肺组织NBL1 mRNA水平分别下降了70%、81%和89%,蛋白水平分别下降了36%、78%和99%,而NBL1血浆浓度由对照组的(2.82±0.58)μg·L-1分别下降为(1.90±0.55)μg·L-1、(1.51±0.43)μg·L-1、(0.64±0.34)μg·L-1,且与肺血流动力学指标及右室肥厚程度均呈明显负相关;免疫组织化学染色显示,对照组NBL1主要定位于肺小动脉,而MCT组重构肺小动脉鲜有表达;细胞实验发现,NBL1能明显抑制BMP2/4对肺动脉内皮细胞BMP信号通路的激活.结论 NBL1的表达水平在MCT诱导的PAH中逐渐降低,说明NBL1或在肺血管重构中发挥重要的作用,而其血浆水平可能是PAH潜在的生物标志物.Aim To study the expression pattern of neuroblastoma, suppression of tumorigenicity 1 (NBL1) in pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). Methods Forty rats were randomly allocated into control group ( n =10) and MCT group ( n =30). Intraperitoneally injection of 60mg·kg ^-1 MCT for MCT group or equal volume normal saline for control group was performed. The changes of NBL1 in lungs and plasma of the 3 rd, 4 th and 5 th week after MCT injection were detected respectively. NBL1 levels in rat plasma were detected by enzyme linked immunosorbent assay. Results At the 3 rd, 4 th, and 5 th week after MCT injection, the mRNA level of NBL1 decreased by 70%, 81% and 89%, the protein level decreased by 36%, 78% and 99%, and the plasma concentration of NBL1 decreased from (2.82±0.58)μg·L ^-1 (control rats) to (1.90±0.55)μg·L^-1 ,(1.51±0.43)μg·L^-1 ,(0.64±0.34)μg·L^-1 and presented a negative correlation with pulmonary hemodynamic indices and right ventricular hypertrophy. Immunohistochemical staining demonstrated that NBL1 was mainly expressed in small pulmonary arteries in normal lungs from control group but seldom detected in severely remodeled pulmonary arteries from MCT group. Furthermore, NBL1 significantly inhibited the activation of BMP signal in pulmonary artery endothelial cells induced by BMP2/4. Conclusions NBL1 level demonstrates a stepwise decrease in MCT induced PAH, implying its vital roles in the pulmonary vascular remodeling process and the possibility of NBL1 to be a potential biomarker for PAH.

关 键 词：野百合碱 肺动脉高压 肺血管重构 神经母细胞瘤抑瘤蛋白1 生物标志物 诊断 

分 类 号：R284[医药卫生—中药学] R322[医药卫生—中医学]