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

Lei Wang; Jing Huang; Ruoyang Zhang; Muzhi Zhang; Yu Guo; Yang Liu; Cong Li; Wei Wang; Sun Ying; Jie Liu; Chen Wang

doi:10.1016/j.isci.2023.108199

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

iScience. 2023 Oct 12;26(11):108199. doi: 10.1016/j.isci.2023.108199. eCollection 2023 Nov 17.

Authors

Lei Wang^{1

2}, Jing Huang³, Ruoyang Zhang^{4

2}, Muzhi Zhang^{4

2}, Yu Guo^{4

2}, Yang Liu^{4

2}, Cong Li¹, Wei Wang^{4

2}, Sun Ying^{4

2}, Jie Liu^{4

2}, Chen Wang²

Affiliations

¹ Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an, Shaanxi 710004, China.
² Department of Respiratory Medicine, Capital Medical University, Beijing 100054, P.R. China.
³ Department of Rheumatism and Immunology, The First Affiliated Hospital Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
⁴ Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100054, China.

Abstract

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.

Keywords: Cardiovascular medicine; Molecular medicine; Molecular physiology.