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

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...

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

e To investigate the effect and mechanism of Feixin Decoction （Astragali Radix， PericaeSemen， Carthami Flos， Descurainiae Semen Lepidii Semen， Paeoniae Radix Rubra， etc.） on monocrotalineinduced pulmonary arterial hypertension （PAH） rats based on peroxisome proliferator-activated receptor-γ/nuclearfactor-κB （PPAR -γ/NF -κB） signaling pathway. Methods Forty-eight male SD rats were randomly divided intonormal group，model group，Sildenafil group （0. 025 g · kg-1） and low -，medium - and high - dose of FeixinDecoction groups （11. 7，23. 4，46. 8 g·kg-1） . PAH rat model was established by single intraperitoneal injectionof monocrotaline solution （60 mg·kg-1） . After 1 hour of modeling，the rats were given intragastric administrationonce 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）， pulmonaryartery 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. Theexpression level of α-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 byELISA. The expression levels of PPAR - γ/NF - κB signaling pathway-related proteins were detected byimmunohistochemistry 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 TAPSEwere significantly decreased （P＜0.01） . The wall of pulmonary arterioles was significantly thickened， and thepercentage of wall thickness of pulmonary arterioles to vascular diameter and the percentage of vascular wall area tototal cross-sectional area of pulmonary arterioles were significantly increased （P＜0.01） . The positive expressionrate of α-SMA protein in pulmonary artery was significantly increased （P＜0.01）. The levels of plasma IL-1β，IL-6and TNF-α were significantly increased （P＜0.01） . The positive expression rate of PPAR-γ protein in lung tissuewas significantly decreased （P＜0.01），and the positive expression rate of NF-κB protein was significantly increased（P＜0.01） . The protein expressions of PPAR-γ and IκB-α in lung tissue were significantly down-regulated （P＜0.01） . The protein expression ratio of p-NF-κB/NF-κB was significantly increased （P＜0.01） . Compared with themodel group，RVSP，mPAP，RVHI，RVIDd and RVAWT in each administration group were significantly decreased（P＜0.05，P＜0.01），while PAAT，PAAT/ PET and TAPSE were significantly increased （P＜0.05，P＜0.01） .The thickness of the vascular wall was significantly reduced， and the percentage of the wall thickness of thepulmonary arterioles to the diameter of the blood vessels and the percentage of the vascular wall area to the totalcross-sectional area of the small arteries were significantly reduced （P＜0.05，P＜0.01） . The positive expressionrate of α-SMA protein in pulmonary artery was significantly decreased （P＜0.05，P＜0.01） . The plasma levels ofIL-1β，IL-6 and TNF-α were significantly decreased （P＜0.05，P＜0.01）. The positive expression rate of PPAR-γprotein in lung tissue was significantly increased （P＜0.05，P＜0.01），and the positive expression rate of NF-κBprotein was significantly decreased （P＜0.05，P＜0.01） . The protein expression of PPAR - γ in lung tissue was significantly up-regulated （P＜0.05， P＜0.01）， and the protein expression ratio of p-NF - κB / NF - κB wassignificantly decreased （P＜0.01） . The protein expression of IκB - α in the lung tissue of rats in the high-dosegroup of Feixin Decoction was significantly up-regulated （P＜0.01） . Conclusion Feixin Decoction can improvepulmonary artery pressure，right ventricular dysfunction and pulmonary vascular remodeling in PAH rats induced bymonocrotaline. The mechanism may be related to the regulation of PPAR - γ/NF - κB signaling pathway to inhibitinflammatory response.