IRE-1信号通路在野百合碱诱导大鼠肺动脉高压中的作用

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(mPAP)、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.

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

Objective To investigate the effects of IRE -1 signal pathway in the development of pulmonary arte-rial 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 pres-sure ( mPAP) , average right ventricular pressure ( mRVP) , and the pulmonary vascular remodeling indicators were signif-icant 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 .