PAH is a progressive disease characterized by uncontrolled proliferation of PASMCs. Zinc finger protein A20 is a negative feedback regulatory protein of NF-κB activity. The aim of this study was to evaluate zinc finger protein A20 can alleviate PAH in hypoxia exposed mice. C57BL/6 mice received a tail vein injection of adenovirus-mediated ad-A20 and ad-A20 shRNA were exposed to hypoxia. PASMCs isolated from rat pulmonary arteries were cultured in hypoxia, and were transfection of A20 adenovirus. Pulmonary hemodynamic parameters were measured by right heart catheterization. Pulmonary vascular morphological changes were analyzed by HE and α-SMA staining. The expression changes of A20, NF-κB and its downstream protein were detected. The expression of phospho-p65 was increased with the prolongation of hypoxia time. The expression of A20 in lung tissue of chronic hypoxia group decreased with the prolongation of hypoxia time. Adenovirus-mediated A20 (ad-A20) overexpression significantly attenuated the abnormally increased RVSP, RV/(LV + S) ratio, WT%, WA%, α-SMA and the pulmonary vessel muscularization. Ad-A20 treatment markedly attenuated the degradation of phospho-p65 and inhibited the induction of phospho-IκBα induced by hypoxia treatment. Furthermore, silencing A20 abolished the protection by anti-inflammatory activity and the inhibitory effect on cell proliferation. We showed that Zinc finger protein A20 can block NF-κB signaling pathway, alleviates the hypoxia-induced abnormal elevation of pulmonary arterial pressure, hyperproliferation of PASMCs and the pulmonary vascular remodeling.

中文翻译：

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A20 通过抑制 NF-κB 激活和肺动脉平滑肌细胞增殖来减轻缺氧引起的肺动脉高压

PAH 是一种进行性疾病，其特征是 PASMC 增殖失控。锌指蛋白A20是NF-κB活性的负反馈调节蛋白。本研究的目的是评估锌指蛋白 A20 是否可以缓解缺氧小鼠的 PAH。 C57BL/6 小鼠尾静脉注射腺病毒介导的 ad-A20，并将 ad-A20 shRNA 暴露于缺氧环境。从大鼠肺动脉中分离出PASMCs，缺氧培养，并转染A20腺病毒。通过右心导管插入术测量肺血流动力学参数。通过HE和α-SMA染色分析肺血管形态变化。检测A20、NF-κB及其下游蛋白的表达变化。磷酸化p65的表达随着缺氧时间的延长而增加。慢性缺氧组肺组织中A20的表达随着缺氧时间的延长而降低。腺病毒介导的 A20 (ad-A20) 过表达显着减弱了异常增加的 RVSP、RV/(LV + S) 比率、WT%、WA%、α-SMA 和肺血管肌化。 Ad-A20 处理显着减弱了磷酸-p65 的降解，并抑制了缺氧处理诱导的磷酸-IκBα 的诱导。此外，沉默A20会消除抗炎活性的保护作用和对细胞增殖的抑制作用。我们发现锌指蛋白A20可以阻断NF-κB信号通路，缓解缺氧引起的肺动脉压异常升高、PASMCs过度增殖和肺血管重塑。