IRE-1信号通路在野百合碱诱导大鼠肺动脉高压中的作用  

The mechanism study of the IRE-1 signal pathway in the development of pulmonary arterial hypertension in rats

作　　者：王捷[1] 龙梅[2] 李倩[3] 阿里旦·艾尔肯[3] 武云[3] 

机构地区：[1]新疆医科大学第一附属医院药学部,新疆乌鲁木齐830011 [2]新疆医科大学基础医学院,新疆乌鲁木齐830011 [3]新疆医科大学第一附属医院全科医学科,新疆乌鲁木齐830011

出　　处：《广东医学》2017年第3期345-348,共4页Guangdong Medical Journal

基　　金：新疆维吾尔自治区自然科学基金青年科学基金项目(编号:2014211C071)

摘　　要：目的探讨抑制内质网应激肌醇必需酶-1(IRE-1)信号通路在野百合碱诱导大鼠肺动脉高压发生、发展中的作用机制。方法选择Wistar雄性大鼠,随机分为正常对照组、模型组、药物治疗组。采用一次性腹腔注射野百合碱的方法建立肺动脉高压模型。药物治疗组在建模2周后给予灌服4-苯基丁酸2周。检测各组大鼠血流动力学、病理形态学及IRE-1信号通路中关键因子葡萄糖调节蛋白78(GRP78)、IRE-1α的mRNA相对表达量。结果腹腔注射野百合碱建立肺动脉高压模型后,模型组平均肺动脉压力(m PAP)、平均右心室压力(mRVP)较正常对照组显著升高(P<0.001),病理肺血管重塑指标较正常对照组增高(P<0.001),GRP78和IRE-1αmRNA相对表达量较正常对照组升高(P<0.05,P<0.001)。经过化学分子伴侣4-苯基丁酸干预后,药物治疗组血流动力学指标较模型组减低(P<0.01),但未恢复到正常对照组水平(P<0.001);病理检测肺小动脉中膜厚度、管壁面积/管总面积与模型组相比减少(P<0.001),可恢复到正常对照组水平(P>0.05),右室肥厚指数与模型组相比减少(P<0.001),未恢复到正常对照组水平(P<0.001);GRP78、IRE-1α的mRNA相对表达量较模型组降低(P<0.05,P<0.001),可恢复到正常对照组水平(P>0.05)。结论内质网应激IRE-1信号通路在肺动脉高压发生、发展中发挥重要作用,通过化学分子伴侣4-苯基丁酸的抑制,可以有效降低肺动脉高压,减轻肺小动脉重塑。Objective To investigate the effects of IRE- 1 signal pathway in the development of pulmonary arterial hypertension（ PAH） in rats. Methods Wistar rats were randomly divided into normal control group,PAH model group,and treatment group. The PAH model in rats was established by the method of bolus intraperitoneal injection of monocrotaline. And 4- phenylbutyric acid（ 4- PBA） was continuously administrated two weeks after modeling in the treatment group. The parameters of hemodynamics,pathology and the quantitative results of mRNA expression in IRE-signaling pathway were tested in 3 groups. Results After the intervention of 4- PBA,the mean pulmonary artery pressure（ m PAP）,average right ventricular pressure（ mRVP）,and the pulmonary vascular remodeling indicators were significant reduced in treatment group compare with the PAH model group（ P〈0. 01）. Furthermore,the mRNA expression of the key factors of IRE- 1 signaling pathway,GRP78 and Ire- 1α,were significant reduced in treatment group compare with the PAH model group（ P〈0. 01）. Conclusion Endoplasmic reticulum（ ER） stress induced by IRE- 1 signaling pathway plays a significant role in the occurrence and development of pulmonary hypertension. Additionally,we show that the inhibition of IRE- 1 signal pathway in ER stress has the potential influence on reducing pulmonary artery pressure and lung small artery remodeling.

关 键 词：肺动脉高压 内质网应激 4-苯基丁酸 IRE-1信号通路 

分 类 号：R977.4[医药卫生—药品]