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首页> 外文期刊>American Journal of Physiology >Statin-mediated correction of STAT1 signaling and inducible nitric oxide synthase expression in cystic fibrosis epithelial cells.
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Statin-mediated correction of STAT1 signaling and inducible nitric oxide synthase expression in cystic fibrosis epithelial cells.

机译：他汀介导的STAT1信号转导和囊性纤维化上皮细胞中可诱导的一氧化氮合酶表达的校正。

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摘要

The expression of the inducible form of nitric oxide synthase (NOS2) is reduced in cystic fibrosis (CF) epithelium despite the presence of aggressive inflammation. A potential mechanism for reduced NOS2 expression in CF is diminished signal transducer and activator of transcription-1 (STAT1) activity, possibly due to an increase in expression of protein inhibitor of activated STAT1 (PIAS1). Previous evidence also suggests that NOS2 expression can be negatively regulated by increased activation of the GTPase RhoA, leading to the hypothesis that CF-related increases in PIAS1 expression and altered STAT1 signaling may be mediated by Rho GTPase function. Consistent with this hypothesis, data demonstrate increased expression of RhoA in two models of CF epithelium with a proportional increase in the active GTP-bound RhoA. Mouse embryonic fibroblasts null for p190B Rho GTPase-activating protein exhibit increased RhoA protein content and activation, similar to what is observed in CF models, and also exhibit CF-like alterations in STAT1 regulation, including decreased STAT1 activation, increased PIAS1 protein expression, and reduced NOS2 induction, implicating RhoA-mediated signaling in CF-related STAT1 alterations. Inhibition of the Rho GTPase pathway at the level of isoprenoid/cholesterol synthesis with mevastatin reduces PIAS1 expression, increases STAT1 activation, and restores NOS2 expression in models of CF epithelium, suggesting that pharmacological inhibition of the isoprenoid synthesis/Rho GTPase pathway may represent a potential avenue for therapeutic intervention for CF.
机译：尽管存在侵袭性炎症，但在囊性纤维化（CF）上皮中可诱导型一氧化氮合酶（NOS2）的表达降低。减少CF中NOS2表达的潜在机制是信号转导和转录激活因子1（STAT1）的活性降低，这可能是由于激活的STAT1（PIAS1）的蛋白抑制剂表达增加所致。先前的证据还表明，GTPase RhoA的激活增加可以使NOS2表达受到负调控，从而得出这样的假设：PIhos中CF相关的增加和STAT1信号通路的改变可能是由R​​ho GTPase功能介导的。与该假设一致，数据表明在两种CF上皮模型中RhoA的表达增加，而与活性GTP结合的RhoA则成比例增加。 p190B Rho GTPase激活蛋白无效的小鼠胚胎成纤维细胞显示RhoA蛋白含量和激活增加，类似于在CF模型中观察到的，并且在STAT1调节中也表现出CF样变化，包括STAT1激活降低，PIAS1蛋白表达增加和降低NOS2诱导，这牵涉RhoA介导的CF相关STAT1改变。用美伐他汀在类异戊二烯/胆固醇合成水平上抑制Rho GTPase途径可降低CF上皮模型中的PIAS1表达，增加STAT1激活并恢复NOS2表达，表明对类异戊二烯合成/ Rho GTPase途径的药理学抑制作用可能代表了潜在的潜力CF的治疗干预途径。

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