Endothelial major vault protein alleviates vascular remodeling via promoting Parkin-mediated mitophagy
Abstract Many important vascular diseases including neointimal hyperplasia and atherosclerosis are characterized by the endothelial cell (EC) injury-initiated pathological vascular remodeling. However, the endogenous regulatory mechanisms underlying it are not fully understood. The present study inv...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59644-y |
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| author | Bin Jiang Fan Bai Yunfu Hu Yu Ren Yuan Su Wanxuan Song Kunxin Xie Dongdong Wang Junlu Pan Yuying Liu Yuxin Feng Xiaoyu Li Hanwen Zhang Xudong Zhu Hui Bai Qing Yang Jingjing Ben Qi Chen |
| author_facet | Bin Jiang Fan Bai Yunfu Hu Yu Ren Yuan Su Wanxuan Song Kunxin Xie Dongdong Wang Junlu Pan Yuying Liu Yuxin Feng Xiaoyu Li Hanwen Zhang Xudong Zhu Hui Bai Qing Yang Jingjing Ben Qi Chen |
| author_sort | Bin Jiang |
| collection | DOAJ |
| description | Abstract Many important vascular diseases including neointimal hyperplasia and atherosclerosis are characterized by the endothelial cell (EC) injury-initiated pathological vascular remodeling. However, the endogenous regulatory mechanisms underlying it are not fully understood. The present study investigates regulatory role of major vault protein (MVP) in the pathogenesis of vascular remodeling via controlling EC injury. By generating male murine vascular disease models, we find that ablation of endothelial MVP increases neointima formation and promotes atherosclerosis. Mechanistically, MVP directly binds with Parkin and inhibits the ubiquitination and proteasomal degradation of Parkin by dissociating the E3 ligase NEDD4L from Parkin, leading to activation of Parkin-mediated mitophagy pathway in the EC. Genetic modulation of endothelial MVP and Parkin influences the mitophagy, apoptosis, and neointima formation. These results demonstrate that MVP acts as an intracellular regulator promoting Parkin-mediated mitophagy. Our findings suggest that MVP/NEDD4L/Parkin axis may serve as the therapeutic target for treating intimal hyperplasia and atherosclerosis. |
| format | Article |
| id | doaj-art-1e58c2dab765439faa406259fb25c4c9 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1e58c2dab765439faa406259fb25c4c92025-08-20T01:49:48ZengNature PortfolioNature Communications2041-17232025-05-0116112010.1038/s41467-025-59644-yEndothelial major vault protein alleviates vascular remodeling via promoting Parkin-mediated mitophagyBin Jiang0Fan Bai1Yunfu Hu2Yu Ren3Yuan Su4Wanxuan Song5Kunxin Xie6Dongdong Wang7Junlu Pan8Yuying Liu9Yuxin Feng10Xiaoyu Li11Hanwen Zhang12Xudong Zhu13Hui Bai14Qing Yang15Jingjing Ben16Qi Chen17Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Forensic Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityDepartment of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical UniversityAbstract Many important vascular diseases including neointimal hyperplasia and atherosclerosis are characterized by the endothelial cell (EC) injury-initiated pathological vascular remodeling. However, the endogenous regulatory mechanisms underlying it are not fully understood. The present study investigates regulatory role of major vault protein (MVP) in the pathogenesis of vascular remodeling via controlling EC injury. By generating male murine vascular disease models, we find that ablation of endothelial MVP increases neointima formation and promotes atherosclerosis. Mechanistically, MVP directly binds with Parkin and inhibits the ubiquitination and proteasomal degradation of Parkin by dissociating the E3 ligase NEDD4L from Parkin, leading to activation of Parkin-mediated mitophagy pathway in the EC. Genetic modulation of endothelial MVP and Parkin influences the mitophagy, apoptosis, and neointima formation. These results demonstrate that MVP acts as an intracellular regulator promoting Parkin-mediated mitophagy. Our findings suggest that MVP/NEDD4L/Parkin axis may serve as the therapeutic target for treating intimal hyperplasia and atherosclerosis.https://doi.org/10.1038/s41467-025-59644-y |
| spellingShingle | Bin Jiang Fan Bai Yunfu Hu Yu Ren Yuan Su Wanxuan Song Kunxin Xie Dongdong Wang Junlu Pan Yuying Liu Yuxin Feng Xiaoyu Li Hanwen Zhang Xudong Zhu Hui Bai Qing Yang Jingjing Ben Qi Chen Endothelial major vault protein alleviates vascular remodeling via promoting Parkin-mediated mitophagy Nature Communications |
| title | Endothelial major vault protein alleviates vascular remodeling via promoting Parkin-mediated mitophagy |
| title_full | Endothelial major vault protein alleviates vascular remodeling via promoting Parkin-mediated mitophagy |
| title_fullStr | Endothelial major vault protein alleviates vascular remodeling via promoting Parkin-mediated mitophagy |
| title_full_unstemmed | Endothelial major vault protein alleviates vascular remodeling via promoting Parkin-mediated mitophagy |
| title_short | Endothelial major vault protein alleviates vascular remodeling via promoting Parkin-mediated mitophagy |
| title_sort | endothelial major vault protein alleviates vascular remodeling via promoting parkin mediated mitophagy |
| url | https://doi.org/10.1038/s41467-025-59644-y |
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