NDRG1 Targets TAF15 to Promote Endothelial Dysfunction and Hypoxia-Induced Pulmonary Hypertension

作者：Chengwei Li, Liang Dong, Ning Zhu, Xiujuan Zhang, Ruzetuoheti Yiminniyaze, Gulinuer Wumaier, Xiaomin Wei, Jing Li, Junzhu Lv, Jingwen Xia, Shuanghui Li, Shuanghui Li, Yuzhen Zeng, Jing Wang, Daibing Zhou, Shengqing Li, Shengqing Li · 发表于：Research Square · 年份：2021 · DOI：10.21203/rs.3.rs-794105/v1 · 研究领域：Mechanisms of cancer metastasis、Pulmonary Hypertension Research and Treatments、Magnesium in Health and Disease

Abstract Background: The mechanism underlying vascular remodeling of hypoxia-induced pulmonary hypertension (HPH) is not fully elucidated. We hypothesized that hypoxia promotes expression of N-myc downstream regulated gene-1 (NDRG1) in human pulmonary arterial endothelial cells (HPAECs), which in turn leads to endothelial dysfunction and contributing to HPH. Methods: Lung samples were obtained from qualified patients and HPH rat models. Quantitative polymerase chain reactions, western blotting and immunohistochemistry were used to measure the expression of NDRG1. EdU incorporation assays, cell counting kit-8 (CCK-8) assays, transwell migration assays, and matrigel assays were conducted to detect the role of NDRG1 in HPACE function in vitro . HPH models were established in SD rats and were treated with plasmids expressing short hairpin RNAs (shRNAs) to silence NDRG1 . The candidate binding partner(s) of NDRG1 was screened and validated via co-immunoprecipitation and immunofluorescence staining. Results: NDRG1 is up-regulated by hypoxia in a time-dependent manner in HPAECs. Expression of NDRG1 was increased in lung tissues of HPH patient and rat model. In vitro , silencing NDRG1 attenuated proliferation, migration and tube formation of HPAECs under hypoxia, while NDRG1 over-expression promoted these behaviors of HPAECs in normoxia. NDRG1 knock-down alleviated vascular remodeling and right ventricular hypertrophy in rat models of HPH. NDRG1 can directly interact with TATA-box bi...