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NDRG1 promotes endothelial dysfunction and hypoxia-induced pulmonary hypertension by targeting TAF15

BACKGROUND: Pulmonary hypertension (PH) represents a threatening pathophysiologic state that can be induced by chronic hypoxia and is characterized by extensive vascular remodeling. However, the mechanism underlying hypoxia-induced vascular remodeling is not fully elucidated. METHODS AND RESULTS: By...

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Autores principales: Li, Chengwei, Lv, Junzhu, Wumaier, Gulinuer, Zhao, Yu, Dong, Liang, Zeng, Yuzhen, Zhu, Ning, Zhang, Xiujuan, Wang, Jing, Xia, Jingwen, Li, Shengqing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599394/
https://www.ncbi.nlm.nih.gov/pubmed/37885911
http://dx.doi.org/10.1093/pcmedi/pbad024
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author Li, Chengwei
Lv, Junzhu
Wumaier, Gulinuer
Zhao, Yu
Dong, Liang
Zeng, Yuzhen
Zhu, Ning
Zhang, Xiujuan
Wang, Jing
Xia, Jingwen
Li, Shengqing
author_facet Li, Chengwei
Lv, Junzhu
Wumaier, Gulinuer
Zhao, Yu
Dong, Liang
Zeng, Yuzhen
Zhu, Ning
Zhang, Xiujuan
Wang, Jing
Xia, Jingwen
Li, Shengqing
author_sort Li, Chengwei
collection PubMed
description BACKGROUND: Pulmonary hypertension (PH) represents a threatening pathophysiologic state that can be induced by chronic hypoxia and is characterized by extensive vascular remodeling. However, the mechanism underlying hypoxia-induced vascular remodeling is not fully elucidated. METHODS AND RESULTS: By using quantitative polymerase chain reactions, western blotting, and immunohistochemistry, we demonstrate that the expression of N-myc downstream regulated gene-1 (NDRG1) is markedly increased in hypoxia-stimulated endothelial cells in a time-dependent manner as well as in human and rat endothelium lesions. To determine the role of NDRG1 in endothelial dysfunction, we performed loss-of-function studies using NDRG1 short hairpin RNAs and NDRG1 over-expression plasmids. In vitro, silencing NDRG1 attenuated proliferation, migration, and tube formation of human pulmonary artery endothelial cells (HPAECs) under hypoxia, while NDRG1 over-expression promoted these behaviors of HPAECs. Mechanistically, NDRG1 can directly interact with TATA-box binding protein associated factor 15 (TAF15) and promote its nuclear localization. Knockdown of TAF15 abrogated the effect of NDRG1 on the proliferation, migration and tube formation capacity of HPAECs. Bioinformatics studies found that TAF15 was involved in regulating PI3K-Akt, p53, and hypoxia-inducible factor 1 (HIF-1) signaling pathways, which have been proved to be PH-related pathways. In addition, vascular remodeling and right ventricular hypertrophy induced by hypoxia were markedly alleviated in NDRG1 knock-down rats compared with their wild-type littermates. CONCLUSIONS: Taken together, our results indicate that hypoxia-induced upregulation of NDRG1 contributes to endothelial dysfunction through targeting TAF15, which ultimately contributes to the development of hypoxia-induced PH.
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spelling pubmed-105993942023-10-26 NDRG1 promotes endothelial dysfunction and hypoxia-induced pulmonary hypertension by targeting TAF15 Li, Chengwei Lv, Junzhu Wumaier, Gulinuer Zhao, Yu Dong, Liang Zeng, Yuzhen Zhu, Ning Zhang, Xiujuan Wang, Jing Xia, Jingwen Li, Shengqing Precis Clin Med Research Article BACKGROUND: Pulmonary hypertension (PH) represents a threatening pathophysiologic state that can be induced by chronic hypoxia and is characterized by extensive vascular remodeling. However, the mechanism underlying hypoxia-induced vascular remodeling is not fully elucidated. METHODS AND RESULTS: By using quantitative polymerase chain reactions, western blotting, and immunohistochemistry, we demonstrate that the expression of N-myc downstream regulated gene-1 (NDRG1) is markedly increased in hypoxia-stimulated endothelial cells in a time-dependent manner as well as in human and rat endothelium lesions. To determine the role of NDRG1 in endothelial dysfunction, we performed loss-of-function studies using NDRG1 short hairpin RNAs and NDRG1 over-expression plasmids. In vitro, silencing NDRG1 attenuated proliferation, migration, and tube formation of human pulmonary artery endothelial cells (HPAECs) under hypoxia, while NDRG1 over-expression promoted these behaviors of HPAECs. Mechanistically, NDRG1 can directly interact with TATA-box binding protein associated factor 15 (TAF15) and promote its nuclear localization. Knockdown of TAF15 abrogated the effect of NDRG1 on the proliferation, migration and tube formation capacity of HPAECs. Bioinformatics studies found that TAF15 was involved in regulating PI3K-Akt, p53, and hypoxia-inducible factor 1 (HIF-1) signaling pathways, which have been proved to be PH-related pathways. In addition, vascular remodeling and right ventricular hypertrophy induced by hypoxia were markedly alleviated in NDRG1 knock-down rats compared with their wild-type littermates. CONCLUSIONS: Taken together, our results indicate that hypoxia-induced upregulation of NDRG1 contributes to endothelial dysfunction through targeting TAF15, which ultimately contributes to the development of hypoxia-induced PH. Oxford University Press 2023-10-09 /pmc/articles/PMC10599394/ /pubmed/37885911 http://dx.doi.org/10.1093/pcmedi/pbad024 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the West China School of Medicine & West China Hospital of Sichuan University. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Research Article
Li, Chengwei
Lv, Junzhu
Wumaier, Gulinuer
Zhao, Yu
Dong, Liang
Zeng, Yuzhen
Zhu, Ning
Zhang, Xiujuan
Wang, Jing
Xia, Jingwen
Li, Shengqing
NDRG1 promotes endothelial dysfunction and hypoxia-induced pulmonary hypertension by targeting TAF15
title NDRG1 promotes endothelial dysfunction and hypoxia-induced pulmonary hypertension by targeting TAF15
title_full NDRG1 promotes endothelial dysfunction and hypoxia-induced pulmonary hypertension by targeting TAF15
title_fullStr NDRG1 promotes endothelial dysfunction and hypoxia-induced pulmonary hypertension by targeting TAF15
title_full_unstemmed NDRG1 promotes endothelial dysfunction and hypoxia-induced pulmonary hypertension by targeting TAF15
title_short NDRG1 promotes endothelial dysfunction and hypoxia-induced pulmonary hypertension by targeting TAF15
title_sort ndrg1 promotes endothelial dysfunction and hypoxia-induced pulmonary hypertension by targeting taf15
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599394/
https://www.ncbi.nlm.nih.gov/pubmed/37885911
http://dx.doi.org/10.1093/pcmedi/pbad024
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