發(fā)布時間：2018-11-20 06:38

【摘要】：目的探討抑制內(nèi)質(zhì)網(wǎng)應(yīng)激肌醇必需酶-1(IRE-1)信號通路在野百合堿誘導(dǎo)大鼠肺動脈高壓發(fā)生、發(fā)展中的作用機制。方法選擇Wistar雄性大鼠,隨機分為正常對照組、模型組、藥物治療組。采用一次性腹腔注射野百合堿的方法建立肺動脈高壓模型。藥物治療組在建模2周后給予灌服4-苯基丁酸2周。檢測各組大鼠血流動力學(xué)、病理形態(tài)學(xué)及IRE-1信號通路中關(guān)鍵因子葡萄糖調(diào)節(jié)蛋白78(GRP78)、IRE-1α的mRNA相對表達(dá)量。結(jié)果腹腔注射野百合堿建立肺動脈高壓模型后,模型組平均肺動脈壓力(m PAP)、平均右心室壓力(mRVP)較正常對照組顯著升高(P0.001),病理肺血管重塑指標(biāo)較正常對照組增高(P0.001),GRP78和IRE-1αmRNA相對表達(dá)量較正常對照組升高(P0.05,P0.001)。經(jīng)過化學(xué)分子伴侶4-苯基丁酸干預(yù)后,藥物治療組血流動力學(xué)指標(biāo)較模型組減低(P0.01),但未恢復(fù)到正常對照組水平(P0.001);病理檢測肺小動脈中膜厚度、管壁面積/管總面積與模型組相比減少(P0.001),可恢復(fù)到正常對照組水平(P0.05),右室肥厚指數(shù)與模型組相比減少(P0.001),未恢復(fù)到正常對照組水平(P0.001);GRP78、IRE-1α的mRNA相對表達(dá)量較模型組降低(P0.05,P0.001),可恢復(fù)到正常對照組水平(P0.05)。結(jié)論內(nèi)質(zhì)網(wǎng)應(yīng)激IRE-1信號通路在肺動脈高壓發(fā)生、發(fā)展中發(fā)揮重要作用,通過化學(xué)分子伴侶4-苯基丁酸的抑制,可以有效降低肺動脈高壓,減輕肺小動脈重塑。
[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 偽 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 偽 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 偽 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.
【作者單位】： 新疆醫(yī)科大學(xué)第一附屬醫(yī)院藥學(xué)部;新疆醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院;新疆醫(yī)科大學(xué)第一附屬醫(yī)院全科醫(yī)學(xué)科;
【基金】：新疆維吾爾自治區(qū)自然科學(xué)基金青年科學(xué)基金項目(編號:2014211C071)
【分類號】：R544.1

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