IRE-1信号通路在野百合碱诱导大鼠肺动脉高压中的作用
发布时间：2018-11-20 06:38
【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(P0.001),病理肺血管重塑指标较正常对照组增高(P0.001),GRP78和IRE-1αmRNA相对表达量较正常对照组升高(P0.05,P0.001)。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(P0.01),但未恢复到正常对照组水平(P0.001);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(P0.001),可恢复到正常对照组水平(P0.05),右室肥厚指数与模型组相比减少(P0.001),未恢复到正常对照组水平(P0.001);GRP78、IRE-1α的mRNA相对表达量较模型组降低(P0.05,P0.001),可恢复到正常对照组水平(P0.05)。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。
[Abstract]:Objective to investigate the mechanism of inhibition of endoplasmic reticulum stress inositol essential enzyme 1 (IRE-1) signaling pathway in monocrotaline induced pulmonary hypertension in rats. Methods male Wistar rats were randomly divided into normal control group, model group and drug treatment group. Pulmonary hypertension model was established by a single intraperitoneal injection of monocrotaline. The drug treatment group was given 4-phenyl butyric acid for 2 weeks after modeling. The relative expression of glucose regulatory protein 78 (GRP78) and IRE-1 伪 in IRE-1 signaling pathway and hemodynamics were measured. Results after intraperitoneal injection of monocrotaline, the mean pulmonary artery pressure (m PAP),) and right ventricular pressure (mRVP) in the model group were significantly higher than those in the control group (P0.001). The pathological pulmonary vascular remodeling index was higher than that of the normal control group (P0.001), and the relative expression of GRP78 and IRE-1 伪 mRNA was higher than that of the normal control group (P0.05, P0.001). After the intervention of 4-phenylbutyric acid, the hemodynamic index of the drug treatment group was lower than that of the model group (P0.01), but did not return to the normal control level (P0.001). Compared with the model group, the thickness of medial membrane of pulmonary arteriole, the area of the wall / the total area of the tube were decreased (P0.001), and the index of right ventricular hypertrophy was decreased (P0.001) in the normal control group (P0.05). Did not return to the normal control level (P0.001); The relative mRNA expression of GRP78,IRE-1 伪 was lower than that of the model group (P0.05, P0.001), and could return to the normal control level (P0.05). Conclusion endoplasmic reticulum stress IRE-1 signaling pathway plays an important role in the pathogenesis and development of pulmonary hypertension. Inhibition of 4-phenylbutyric acid by chemical molecular chaperones can effectively reduce pulmonary hypertension and alleviate pulmonary arterioles remodeling.
【作者单位】： 新疆医科大学第一附属医院药学部;新疆医科大学基础医学院;新疆医科大学第一附属医院全科医学科;
【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)
【分类号】：R544.1
[Abstract]:Objective to investigate the mechanism of inhibition of endoplasmic reticulum stress inositol essential enzyme 1 (IRE-1) signaling pathway in monocrotaline induced pulmonary hypertension in rats. Methods male Wistar rats were randomly divided into normal control group, model group and drug treatment group. Pulmonary hypertension model was established by a single intraperitoneal injection of monocrotaline. The drug treatment group was given 4-phenyl butyric acid for 2 weeks after modeling. The relative expression of glucose regulatory protein 78 (GRP78) and IRE-1 伪 in IRE-1 signaling pathway and hemodynamics were measured. Results after intraperitoneal injection of monocrotaline, the mean pulmonary artery pressure (m PAP),) and right ventricular pressure (mRVP) in the model group were significantly higher than those in the control group (P0.001). The pathological pulmonary vascular remodeling index was higher than that of the normal control group (P0.001), and the relative expression of GRP78 and IRE-1 伪 mRNA was higher than that of the normal control group (P0.05, P0.001). After the intervention of 4-phenylbutyric acid, the hemodynamic index of the drug treatment group was lower than that of the model group (P0.01), but did not return to the normal control level (P0.001). Compared with the model group, the thickness of medial membrane of pulmonary arteriole, the area of the wall / the total area of the tube were decreased (P0.001), and the index of right ventricular hypertrophy was decreased (P0.001) in the normal control group (P0.05). Did not return to the normal control level (P0.001); The relative mRNA expression of GRP78,IRE-1 伪 was lower than that of the model group (P0.05, P0.001), and could return to the normal control level (P0.05). Conclusion endoplasmic reticulum stress IRE-1 signaling pathway plays an important role in the pathogenesis and development of pulmonary hypertension. Inhibition of 4-phenylbutyric acid by chemical molecular chaperones can effectively reduce pulmonary hypertension and alleviate pulmonary arterioles remodeling.
【作者单位】： 新疆医科大学第一附属医院药学部;新疆医科大学基础医学院;新疆医科大学第一附属医院全科医学科;
【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)
【分类号】：R544.1
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