Culin5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGF
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 angioge...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223022769 |
| _version_ | 1797647840711802880 |
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| author | Lei Wang Jing Huang Ruoyang Zhang Muzhi Zhang Yu Guo Yang Liu Cong Li Wei Wang Sun Ying Jie Liu Chen Wang |
| author_facet | Lei Wang Jing Huang Ruoyang Zhang Muzhi Zhang Yu Guo Yang Liu Cong Li Wei Wang Sun Ying Jie Liu Chen Wang |
| author_sort | Lei Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T15:22:20Z |
| format | Article |
| id | doaj.art-afccc7e7dc774dff9856e60cc20b574d |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-11T15:22:20Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-afccc7e7dc774dff9856e60cc20b574d2023-10-28T05:09:29ZengElsevieriScience2589-00422023-11-012611108199Culin5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGFLei Wang0Jing Huang1Ruoyang Zhang2Muzhi Zhang3Yu Guo4Yang Liu5Cong Li6Wei Wang7Sun Ying8Jie Liu9Chen Wang10Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University (Xibei Hospital), Xi’an, Shaanxi 710004, China; Department of Respiratory Medicine, Capital Medical University, Beijing 100054, P.R. ChinaDepartment of Rheumatism and Immunology, The First Affiliated Hospital Xi’an Jiaotong University, Xi’an, Shaanxi 710061, ChinaDepartment of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100054, China; Department of Respiratory Medicine, Capital Medical University, Beijing 100054, P.R. ChinaDepartment of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100054, China; Department of Respiratory Medicine, Capital Medical University, Beijing 100054, P.R. ChinaDepartment of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100054, China; Department of Respiratory Medicine, Capital Medical University, Beijing 100054, P.R. ChinaDepartment of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100054, China; Department of Respiratory Medicine, Capital Medical University, Beijing 100054, P.R. ChinaDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University (Xibei Hospital), Xi’an, Shaanxi 710004, ChinaDepartment of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100054, China; Department of Respiratory Medicine, Capital Medical University, Beijing 100054, P.R. ChinaDepartment of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100054, China; Department of Respiratory Medicine, Capital Medical University, Beijing 100054, P.R. ChinaDepartment of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100054, China; Department of Respiratory Medicine, Capital Medical University, Beijing 100054, P.R. China; Corresponding authorDepartment of Respiratory Medicine, Capital Medical University, Beijing 100054, P.R. ChinaSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004223022769Cardiovascular medicineMolecular physiologyMolecular medicine |
| spellingShingle | Lei Wang Jing Huang Ruoyang Zhang Muzhi Zhang Yu Guo Yang Liu Cong Li Wei Wang Sun Ying Jie Liu Chen Wang Culin5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGF iScience Cardiovascular medicine Molecular physiology Molecular medicine |
| title | Culin5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGF |
| title_full | Culin5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGF |
| title_fullStr | Culin5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGF |
| title_full_unstemmed | Culin5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGF |
| title_short | Culin5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGF |
| title_sort | culin5 aggravates hypoxic pulmonary hypertension by activating traf6 nf κb hif 1α vegf |
| topic | Cardiovascular medicine Molecular physiology Molecular medicine |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223022769 |
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