Histone deacetylase 3 deletion in alveolar type 2 epithelial cells prevents bleomycin-induced pulmonary fibrosis

作者全名："Xiong, Rui; Geng, Boxin; Jiang, Wenyang; Hu, Yong; Hu, Zhaoyu; Hao, Bo; Li, Ning; Geng, Qing"

作者地址："[Xiong, Rui; Jiang, Wenyang; Hao, Bo; Li, Ning; Geng, Qing] Wuhan Univ, Renmin Hosp, Dept Thorac Surg, Jiefang Rd 238, Wuhan 430060, Peoples R China; [Geng, Boxin] Army Med Univ, Chongqing 430038, Peoples R China; [Hu, Yong; Hu, Zhaoyu] Wuhan Rhegen Biotechnol Co Ltd, Wuhan 430073, Peoples R China"

通信作者："Li, N; Geng, Q (通讯作者)，Wuhan Univ, Renmin Hosp, Dept Thorac Surg, Jiefang Rd 238, Wuhan 430060, Peoples R China."

来源：CLINICAL EPIGENETICS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001100909800001

JCR分区：Q1

影响因子：5.7

年份：2023

卷号：15

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：PF; HDAC3; EMT; Acetylation; GATA3

摘要："BackgroundEpithelial mesenchymal transformation (EMT) in alveolar type 2 epithelial cells (AT2) is closely associated with pulmonary fibrosis (PF). Histone deacetylase 3 (HDAC3) is an important enzyme that regulates protein stability by modulating the acetylation level of non-histones. Here, we aimed to explore the potential role and regulatory mechanisms associated with HDAC3 in PF.MethodsWe quantified HDAC3 expression both in lung tissues from patients with PF and from bleomycin (BLM)-treated mice. HDAC3 was also detected in TGF-beta 1-treated AT2. The mechanistic activity of HDAC3 in pulmonary fibrosis and EMT was also explored.ResultsHDAC3 was highly expressed in lung tissues from patients with PF and bleomycin (BLM)-treated mice, especially in AT2. Lung tissues from AT2-specific HDAC3-deficient mice stimulated with BLM showed alleviative fibrosis and EMT. Upstream of HDAC3, TGF-beta 1/SMAD3 directly promoted HDAC3 transcription. Downstream of HDAC3, we also found that genetic or pharmacologic inhibition of HDAC3 inhibited GATA3 expression at the protein level rather than mRNA. Finally, we found that intraperitoneal administration of RGFP966, a selective inhibitor of HDAC3, could prevent mice from BLM-induced pulmonary fibrosis and EMT.ConclusionTGF-beta 1/SMAD3 directly promoted the transcription of HDAC3, which aggravated EMT in AT2 and pulmonary fibrosis in mice via deacetylation of GATA3 and inhibition of its degradation. Our results suggest that targeting HDAC3 in AT2 may provide a new therapeutic target for the prevention of PF."

基金机构：National Natural Science Foundation of China [82102269]; Central University Basic Research Fund of China [2042021kf0081]; Science Fund for Creative Research Groups of the Natural Science Foundation of Hubei Province [2020CFA027]

基金资助正文："This work was supported by grants from the National Natural Science Foundation of China (No. 82102269), the Central University Basic Research Fund of China (No. 2042021kf0081) and Science Fund for Creative Research Groups of the Natural Science Foundation of Hubei Province (No. 2020CFA027)"