FBXO38 Regulates Nox1 Stability to Reduce Vascular Endothelial Damage Induced by Low Oscillatory Shear Stress
Oxidative stress and endothelial dysfunction are critical drivers of atherosclerosis, but the mechanisms regulating oxidative stress under disturbed flow conditions remain incompletely understood. The ubiquitin–proteasome system, particularly E3 ubiquitin ligases, may play a pivotal role in modulati...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Cardiovascular Therapeutics |
| Online Access: | http://dx.doi.org/10.1155/cdr/4506032 |
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| author | Wan-li Yu Li-wen Deng Huan-huan Li Chun-kai Wang Xiang-yi Zuo Zi-chang Wang Li Meng Lan-xin Wen Wan-zhi Zeng Yu Zhao Xue-hu Wang |
| author_facet | Wan-li Yu Li-wen Deng Huan-huan Li Chun-kai Wang Xiang-yi Zuo Zi-chang Wang Li Meng Lan-xin Wen Wan-zhi Zeng Yu Zhao Xue-hu Wang |
| author_sort | Wan-li Yu |
| collection | DOAJ |
| description | Oxidative stress and endothelial dysfunction are critical drivers of atherosclerosis, but the mechanisms regulating oxidative stress under disturbed flow conditions remain incompletely understood. The ubiquitin–proteasome system, particularly E3 ubiquitin ligases, may play a pivotal role in modulating these processes. FBXO38, an E3 ligase involved in proteasomal degradation, has been implicated in various physiological pathways, but its role in regulating oxidative stress in endothelial cells is unknown. We hypothesized that FBXO38 mitigates endothelial damage induced by low oscillatory shear stress (LOSS) by promoting the ubiquitin–proteasome–dependent degradation of Nox1, a major source of reactive oxygen species (ROS). Using an in vitro LOSS model in human umbilical vein endothelial cells (HUVECs) and an in vivo mouse partial carotid ligation model, we assessed the expression of FBXO38 and Nox1 through quantitative PCR, western blotting, immunofluorescence, and immunohistochemistry. LOSS significantly reduced FBXO38 protein expression (by ~60%, p<0.0001 at 24 h), leading to increased Nox1 protein levels (approximately two-fold, p<0.001) and apoptosis. FBXO38 overexpression markedly attenuated Nox1 accumulation (~50% reduction, p<0.05), reduced ROS production, and improved cell viability under LOSS conditions, whereas FBXO38 knockdown exacerbated these effects. Moreover, FBXO38 directly interacted with Nox1, suggesting a ubiquitin-dependent degradation mechanism. Our results reveal that FBXO38 regulates endothelial oxidative stress by controlling Nox1 stability under disturbed shear stress conditions. Although FBXO38 emerges as a promising candidate for therapeutic targeting, further studies are necessary to validate its potential in preclinical and clinical settings. |
| format | Article |
| id | doaj-art-96c732fb663b40c29dbac9bf29dde821 |
| institution | Kabale University |
| issn | 1755-5922 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cardiovascular Therapeutics |
| spelling | doaj-art-96c732fb663b40c29dbac9bf29dde8212025-08-20T03:48:31ZengWileyCardiovascular Therapeutics1755-59222025-01-01202510.1155/cdr/4506032FBXO38 Regulates Nox1 Stability to Reduce Vascular Endothelial Damage Induced by Low Oscillatory Shear StressWan-li Yu0Li-wen Deng1Huan-huan Li2Chun-kai Wang3Xiang-yi Zuo4Zi-chang Wang5Li Meng6Lan-xin Wen7Wan-zhi Zeng8Yu Zhao9Xue-hu Wang10Department of Vascular SurgeryDepartment of Vascular SurgeryDepartment of Vascular SurgeryDepartment of Vascular SurgeryDepartment of Vascular SurgeryDepartment of Vascular SurgeryDepartment of Vascular SurgeryDepartment of Vascular SurgeryDepartment of Vascular SurgeryDepartment of Vascular SurgeryDepartment of Vascular SurgeryOxidative stress and endothelial dysfunction are critical drivers of atherosclerosis, but the mechanisms regulating oxidative stress under disturbed flow conditions remain incompletely understood. The ubiquitin–proteasome system, particularly E3 ubiquitin ligases, may play a pivotal role in modulating these processes. FBXO38, an E3 ligase involved in proteasomal degradation, has been implicated in various physiological pathways, but its role in regulating oxidative stress in endothelial cells is unknown. We hypothesized that FBXO38 mitigates endothelial damage induced by low oscillatory shear stress (LOSS) by promoting the ubiquitin–proteasome–dependent degradation of Nox1, a major source of reactive oxygen species (ROS). Using an in vitro LOSS model in human umbilical vein endothelial cells (HUVECs) and an in vivo mouse partial carotid ligation model, we assessed the expression of FBXO38 and Nox1 through quantitative PCR, western blotting, immunofluorescence, and immunohistochemistry. LOSS significantly reduced FBXO38 protein expression (by ~60%, p<0.0001 at 24 h), leading to increased Nox1 protein levels (approximately two-fold, p<0.001) and apoptosis. FBXO38 overexpression markedly attenuated Nox1 accumulation (~50% reduction, p<0.05), reduced ROS production, and improved cell viability under LOSS conditions, whereas FBXO38 knockdown exacerbated these effects. Moreover, FBXO38 directly interacted with Nox1, suggesting a ubiquitin-dependent degradation mechanism. Our results reveal that FBXO38 regulates endothelial oxidative stress by controlling Nox1 stability under disturbed shear stress conditions. Although FBXO38 emerges as a promising candidate for therapeutic targeting, further studies are necessary to validate its potential in preclinical and clinical settings.http://dx.doi.org/10.1155/cdr/4506032 |
| spellingShingle | Wan-li Yu Li-wen Deng Huan-huan Li Chun-kai Wang Xiang-yi Zuo Zi-chang Wang Li Meng Lan-xin Wen Wan-zhi Zeng Yu Zhao Xue-hu Wang FBXO38 Regulates Nox1 Stability to Reduce Vascular Endothelial Damage Induced by Low Oscillatory Shear Stress Cardiovascular Therapeutics |
| title | FBXO38 Regulates Nox1 Stability to Reduce Vascular Endothelial Damage Induced by Low Oscillatory Shear Stress |
| title_full | FBXO38 Regulates Nox1 Stability to Reduce Vascular Endothelial Damage Induced by Low Oscillatory Shear Stress |
| title_fullStr | FBXO38 Regulates Nox1 Stability to Reduce Vascular Endothelial Damage Induced by Low Oscillatory Shear Stress |
| title_full_unstemmed | FBXO38 Regulates Nox1 Stability to Reduce Vascular Endothelial Damage Induced by Low Oscillatory Shear Stress |
| title_short | FBXO38 Regulates Nox1 Stability to Reduce Vascular Endothelial Damage Induced by Low Oscillatory Shear Stress |
| title_sort | fbxo38 regulates nox1 stability to reduce vascular endothelial damage induced by low oscillatory shear stress |
| url | http://dx.doi.org/10.1155/cdr/4506032 |
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