In:
Precision Clinical Medicine, Oxford University Press (OUP)
Kurzfassung:
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. By using quantitative polymerase chain reactions, western blotting and immunohistochemistry, we demonstrate that the expression of NDRG1 is markedly increased in hypoxia-stimulated endothelial cells with 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 (shRNAs) 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. Silence of TAF15 restored the increased proliferation, migration and tube formation. Bioinformatics study found that TAF15 was involved in regulating PI3K-Akt, p53 and HIF-1 signaling pathways, which have been proved as pulmonary hypertension related pathway. 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. Taken together, our results indicate that hypoxia-induced up-regulation of NDRG1 contributes to endothelial dysfunction through targeting TAF15, which ultimately contributes to the development of HPH.
Materialart:
Online-Ressource
ISSN:
2096-5303
,
2516-1571
DOI:
10.1093/pcmedi/pbad024
Sprache:
Englisch
Verlag:
Oxford University Press (OUP)
Publikationsdatum:
2023
ZDB Id:
2948341-4
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