TGF-β1通过PI3K及ERK信号通路调节肺动脉高压过程中IGFBPs蛋白表达  

IGFBPs are Regulated by TGF-β1 Relying on PI3K and ERK Signaling Pathway in PAH

作　　者：苏星宇[1] 蒋晓敏[1] 陈绍良[1] 

机构地区：[1]南京医科大学附属南京第一医院心血管内科,江苏南京210000

出　　处：《现代生物医学进展》2016年第8期1428-1431,1466,共5页Progress in Modern Biomedicine

基　　金：江苏省临床科技专项基金资助(BL2013001)

摘　　要：目的:探讨大鼠肺动脉高压(PAH)过程中TGF-β1对胰岛素样生长因子结合蛋白(IGFBP)表达调节是否依赖于PI3K及ERK信号通路。方法:取健康成年SD大鼠26只,随机分成2组:PAH组,腹腔注射1%的野百合碱,剂量为60 mg/kg;对照(C)组腹腔注射生理盐水。于4周后超声检测肺动脉平均压力,取肺组织做HE染色,应用NIS-Element系统测量中膜厚度。原代培养肺动脉平滑肌(PASMC)细胞,分别加入TGF-β1及TGF-β1中和抗体后,Western-blot检测IGFBP3,IGFBP5,Smad2/Smad3表达。加入ERK特异性抑制剂PD98059或PI3K抑制剂LY294002,检测IGFBP3,IGFBP5表达。结果:野百合碱处理4周后,肺动脉高压组的平均肺动脉压力及右室/(左室+室间隔)比值显著高于对照组。TGF-β1可显著升高IGFBP3,IGFBP5及p-Smad3的表达(P<0.05),而抑制TGF-β1则可显著降低三种蛋白的表达(P<0.05)。加入LY294002抑制PI3K ERK后,IGFBP3和p-Smad2两种蛋白的表达量显著下调(P<0.05)。加入PD98059抑制ERK后可显著降低IGFBP3及IGFBP5的表达水平(P<0.05)。结论:PAH中TGF-β1升高可通过活化Smad2/Smad3上调IGFBP3和IGFBP5的表达。TGF-β1促进IGFBP3,IGFBP5表达的作用依赖于PI3K及ERK信号通路。To investigate the mechanism of TGF-β1 regulating the expression of insulin-like growth factor binding protein（IGFBP） expression in rats. To determine if the regulation of insulin-like growth factor binding protein（IGFBP） by TGF-β1depends on PI3 K and ERK signaling pathway in rat pulmonary arterial hypertension（PAH）. Methods： Twenty-six SD rats were randomly divided into 2 groups： PAH group, intraperitoneal injection of 1% of monocrotaline. Control（C） groups were injected with saline.Pulmonary artery pressure and HE staining were tested after four weeks. Primary pulmonary artery smooth muscle（PASMC） cells were cultured, IGFBP3, IGFBP5, Smad2 / Smad3 were detected with or without TGF-β1 by Western-blot. After treated with ERK inhibitor PD98059 or PI3 K inhibitor LY294002, IGFBP3, IGFBP5 were detected. Results： Four weeks after treatment, the MPAP in PAH group were higher than control group. The PAH model leads to a significant increase in RV/（LV＋S） and pulmonary artery media thickness.TGF-β1 significantly increased expression of IGFBP3, IGFBP5 and p-Smad3 protein. LY294002 significantly suppressed the expression of IGFBP3 and p-Smad2 protein. What＇s more, PD98059 significantly suppressed the expression of IGFBP3 and IGFBP5. Conclusions：IGFBP5 and IGFBP3 can be regulated by TGF-β1 through activating Smad2 / Smad3, which depends on PI3 K and ERK signaling pathway.

关 键 词：肺动脉高压 TGF-Β信号通路 ERK信号通路 

分 类 号：R544.16[医药卫生—心血管疾病] R-33[医药卫生—内科学]