基于PPAR-γ/NF-κB信号通路探讨肺心汤对野百合碱诱导肺动脉高压大鼠模型的作用及机制  

Exploration of the Effects and Mechanisms of Feixin Decoction on Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats Based on PPAR-γ/NF-κB Signaling Pathway

作　　者：谭骏岚 易健 曹闲雅[1,2] 王飞英 丁蓉珍 戴爱国 TAN Junlan;YI Jian;CAO Xianya;WANG Feiying;DING Rongzhen;DAI Aigu(School of Integrative Chinese and Western Medicine,Hunan University of Chinese Medicine,Changsha 410208 Hunan,China;Hunan Provincial Key Laboratory of Vascular Biology and Translational Medicine,Changsha 410208 Hunan,China;Medical Innovation Experiment Center of the First Affiliated Hospital,Hunan University of Chinese Medicine,Changsha 410021 Hunan,China;Department of Respiratory Diseases,Medical School,Hunan University of Chinese Medicine,Changsha 410208 Hunan,China;Department of Respiratory Medicine,The First Affiliated Hospital,Hunan University of Chinese Medicine,Changsha 410021 Hunan,China)

机构地区：[1]湖南中医药大学中西医结合学院,湖南长沙410208 [2]血管生物学与转化医学湖南省重点实验室,湖南长沙410208 [3]湖南中医药大学第一附属医院医学创新实验中心,湖南长沙410021 [4]湖南中医药大学医学院呼吸疾病研究室,湖南长沙410208 [5]湖南中医药大学第一附属医院呼吸科,湖南长沙410021

出　　处：《中药新药与临床药理》2024年第3期307-316,共10页Traditional Chinese Drug Research and Clinical Pharmacology

基　　金：国家自然科学基金项目(82200066);湖南省自然科学基金项目(2021JJ30017);中国博士后科学基金面上项目(2021M690982);湖南省中医药科研计划重点项目(C2022001);湖南省研究生科学研究创新项目(CX20220823);长沙市自然科学基金项目(kq2202272);湖南中医药大学中西医结合学院-明康中锦联合基金项目(2022MKZJ07)。

摘　　要：目的基于过氧化物酶体增殖物激活受体γ/核因子κB(PPAR-γ/NF-κB)信号通路探讨肺心汤(黄芪、桃仁、红花、葶苈子、赤芍等)对野百合碱诱导肺动脉高压(PAH)大鼠模型的作用及机制。方法将48只雄性SD大鼠随机分为正常组、模型组、西地那非组(0.025 g·kg^(-1))及肺心汤低、中、高剂量组(11.7、23.4、46.8 g·kg^(-1))。采用单次腹腔注射野百合碱溶液(60 mg·kg^(-1))构建PAH大鼠模型。造模1 h后开始灌胃给药,每日1次,连续28 d。检测各组大鼠的血流动力学及超声心动图指标:右心室收缩压(RVSP)、平均肺动脉压(m PAP)、右心肥厚指数(RVHI)、肺动脉加速时间(PAAT)、肺动脉射血时间(PET)、三尖瓣环缩期位移(TAPSE)、右心室舒张末期内径(RVIDd)和右心室前壁厚度(RVAWT);采用HE染色法观察肺小动脉病理改变;免疫荧光法检测大鼠肺动脉中α平滑肌肌动蛋白(α-SMA)表达水平;ELISA法检测血浆白细胞介素1β(IL-1β)、IL-6、肿瘤坏死因子α(TNF-α)水平;免疫组化和Western Blot法检测PPAR-γ/NF-κB信号通路相关蛋白表达水平。结果与正常组相比,模型组大鼠的RVSP、m PAP、RVHI、RVIDd及RVAWT显著升高(P<0.01),PAAT、PAAT/PET、TAPSE均显著降低(P<0.01);肺小动脉血管壁明显增厚,肺小动脉管壁厚度占血管直径的百分比、血管壁面积占小动脉总横截面积的百分比均显著升高(P<0.01);肺动脉中α-SMA蛋白免疫荧光的阳性表达率显著升高(P<0.01);血浆IL-1β、IL-6、TNF-α水平显著升高(P<0.01);肺组织中的PPAR-γ蛋白阳性表达率显著降低(P<0.01),NF-κB蛋白阳性表达率显著升高(P<0.01);肺组织中PPAR-γ、IκB-α蛋白表达显著下调(P<0.01);p-NF-κB/NF-κB蛋白表达比值显著升高(P<0.01)。与模型组比较,各给药组大鼠的RVSP、m PAP、RVHI、RVIDd和RVAWT均显著降低(P<0.05,P<0.01),PAAT、PAAT/PET、TAPSE均显著升高(P<0.05,P<0.01);血管壁厚度明显降低,肺小动脉管壁厚度占血管直�Objective To investigate the effect and mechanism of Feixin Decoction(Astragali Radix,Pericae Semen,Carthami Flos,Descurainiae Semen Lepidii Semen,Paeoniae Radix Rubra,etc.)on monocrotaline-induced pulmonary arterial hypertension(PAH)rats based on peroxisome proliferator-activated receptor-γ/nuclear factor-κB(PPAR-γ/NF-κB)signaling pathway.Methods Forty-eight male SD rats were randomly divided into normal group,model group,Sildenafil group(0.025 g·kg^(-1))and low-,medium-and high-dose of Feixin Decoction groups(11.7,23.4,46.8 g·kg^(-1)).PAH rat model was established by single intraperitoneal injection of monocrotaline solution(60 mg·kg^(-1)).After 1 hour of modeling,the rats were given intragastric administration once a day for 28 days.Hemodynamic and echocardiographic parameters including right ventricular systolic pressure(RVSP),mean pulmonary artery pressure(mPAP),right ventricular hypertrophy index(RVHI),pulmonary artery acceleration time(PAAT),pulmonary artery ejection time(PET),tricuspid annular plane systolic excursion(TAPSE),right ventricular internal diameter(RVIDd)and right ventricular anterior wall thickness(RVAWT)were measured in each group.The pathological changes of pulmonary arterioles were observed by HE staining.The expression level ofα-smooth muscle actin(α-SMA)in rat pulmonary artery was detected by immunofluorescence.The levels of plasma interleukin-1β(IL-1β),IL-6 and tumor necrosis factor-α(TNF-α)were detected by ELISA.The expression levels of PPAR-γ/NF-κB signaling pathway-related proteins were detected by immunohistochemistry and Western Blot.Results Compared with the normal group,the RVSP,mPAP,RVHI,RVIDd and RVAWT of the model group were significantly increased(P<0.01).PAAT,PAAT/PET and TAPSE were significantly decreased(P<0.01).The wall of pulmonary arterioles was significantly thickened,and the percentage of wall thickness of pulmonary arterioles to vascular diameter and the percentage of vascular wall area to total cross-sectional area of pulmonary arterioles were signifi

关 键 词：肺心汤 肺动脉高压 PPAR-γ/NF-κB信号通路 肺血管重塑 炎症反应 大鼠 

分 类 号：R285.5[医药卫生—中药学]