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Culin5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGF

Authors :
Lei Wang
Jing Huang
Ruoyang Zhang
Muzhi Zhang
Yu Guo
Yang Liu
Cong Li
Wei Wang
Sun Ying
Jie Liu
Chen Wang
Source :
iScience, Vol 26, Iss 11, Pp 108199- (2023)
Publication Year :
2023
Publisher :
Elsevier, 2023.

Abstract

Summary: Hypoxic pulmonary hypertension (HPH) lacks effective pharmacologic treatments. Microarray-based gene expression indicates the crucial role of Cullin 5 (Cul 5) in HPH. This study showed that Cul 5 was upregulated in HPH patients and a murine model of HPH. In vitro, Cul 5 promoted the angiogenesis and adhesion capacity of human pulmonary artery endothelial cells (PAECs), which could be mitigated by Cul 5 inactivation mediated by pevonedistat or NEDD8 silence. In vivo, silencing of Cul 5 in the endothelium and Cul 5 inactivation by pevonedistat could also alleviate hypoxic vascular remodeling. Mechanistic research showed that Cul 5 participated in HPH pathogenesis via the TRAF6/NF-κB/HIF-1α/VEGF pathway. Inhibition of the TRAF6/NF-κB/HIF-1α/VEGF pathway could reverse Cul 5-induced human PAEC dysfunction. These findings demonstrate that Cul 5 is an important mediator of HPH via the TRAF6/NF-κB/HIF-1α/VEGF pathway firstly, and could be considered as a potential therapeutic target in the clinical treatment of HPH.

Details

Language :
English
ISSN :
25890042
Volume :
26
Issue :
11
Database :
Directory of Open Access Journals
Journal :
iScience
Publication Type :
Academic Journal
Accession number :
edsdoj.fccc7e7dc774dff9856e60cc20b574d
Document Type :
article
Full Text :
https://doi.org/10.1016/j.isci.2023.108199