Histone deacetylase (HDAC) inhibition was reported to ameliorate lung fibrosis in animal models. However, little is known about the underlying mechanism of HDAC7 in the regulation of CTGF production in lung fibroblasts. The role of HDAC7 in CTGF production caused by ET-1 stimulation in WI-38 cells (human lung fibroblast) was examined. We also evaluated the expression of HDAC7 in the lung of ovalbumin-induced airway fibrosis model. Statistical data were shown as mean ± standard error. ET-1-stimulated CTGF and α-SMA expression was attenuated by small interfering (si)RNA interference of HDAC7. ET-1 promoted HDAC7 translocation from the cytosol to nucleus. ET-1-stimulated CTGF expression was reduced by the transfection of p300 siRNA. ET-1 induced an increase in p300 activity. Furthermore, the acetylation of c-Jun was time-dependently induced by ET-1 stimulation, which was reduced by transfection of either HDAC7 or p300 siRNA. Both transfection of HDAC7 and p300 siRNA suppressed the ET-1-increased activity of AP-1-luciferase. Moreover, the presence of HDAC7 was required for ET-1-stimulated formation of HDAC7, p300, and AP-1 complex and recruitment to the CTGF promoter region. In an ovalbumin-induced airway fibrosis model, the protein level of HDAC7 was increased in the lung tissue, and the distribution of HDAC7 was colocalized with α-SMA-positive cells in the subepithelial layer of the airway. ET-1 activates HDAC7 to initiate AP-1 transcriptional activity by recruiting p300 and eventually promotes the production of CTGF. HDAC7 might play a vital role in airway fibrosis and have the potential to be developed as a therapeutic target.

中文翻译：

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组蛋白去乙酰化酶 7 通过 p300 和激活蛋白 1 激活介导内皮素 1 诱导的人肺成纤维细胞中结缔组织生长因子的表达

据报道，组蛋白去乙酰化酶 (HDAC) 抑制可改善动物模型中的肺纤维化。然而，关于 HDAC7 在调节肺成纤维细胞 CTGF 产生中的潜在机制知之甚少。检查了 HDAC7 在 WI-38 细胞（人肺成纤维细胞）中由 ET-1 刺激引起的 CTGF 产生中的作用。我们还评估了 HDAC7 在卵清蛋白诱导的气道纤维化模型肺中的表达。统计数据显示为平均值±标准误差。ET-1 刺激的 CTGF 和 α-SMA 表达被 HDAC7 的小干扰 (si)RNA 干扰减弱。ET-1 促进 HDAC7 从细胞质到细胞核的易位。p300 siRNA 的转染降低了 ET-1 刺激的 CTGF 表达。ET-1 诱导 p300 活性增加。此外，c-Jun 的乙酰化是由 ET-1 刺激时间依赖性诱导的，通过 HDAC7 或 p300 siRNA 的转染减少。HDAC7 和 p300 siRNA 的转染均抑制了 AP-1-荧光素酶的 ET-1 增加的活性。此外，ET-1 刺激 HDAC7、p300 和 AP-1 复合物的形成以及向 CTGF 启动子区域募集需要 HDAC7 的存在。在卵清蛋白诱导的气道纤维化模型中，肺组织中 HDAC7 的蛋白水平升高，HDAC7 的分布与气道上皮下层的 α-SMA 阳性细胞共定位。ET-1 通过募集 p300 激活 HDAC7 以启动 AP-1 转录活性并最终促进 CTGF 的产生。HDAC7 可能在气道纤维化中发挥重要作用，并有可能被开发为治疗靶点。