Endothelial deubiquinatase YOD1 mediates Ang II-induced vascular endothelial-mesenchymal transition and remodeling by regulating β-catenin

• Published in: Acta pharmacologica Sinica 2024-08, Vol.45 (8), p.1618-1631
• Main Authors: Lin, Wan-te, Jiang, Yu-cheng, Mei, Yi-lin, Chen, Yang-hao, Zheng, Zhao-zheng, Han, Xue, Wu, Gao-jun, Huang, Wei-jian, Ye, Bo-zhi, Liang, Guang
• Format: Article
• Language: English
• Subjects: Angiotensin II - metabolism; Angiotensin II - pharmacology; Animals; beta Catenin - metabolism; Biomedical and Life Sciences; Biomedicine; Endothelial-Mesenchymal Transition; Epithelial-Mesenchymal Transition - drug effects; Human Umbilical Vein Endothelial Cells; Humans; Immunology; Internal Medicine; Male; Medical Microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Pharmacology/Toxicology; Vaccine
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/s41401-024-01278-9

Hypertension is a prominent contributor to vascular injury. Deubiquinatase has been implicated in the regulation of hypertension-induced vascular injury. In the present study we investigated the specific role of deubiquinatase YOD1 in hypertension-induced vascular injury. Vascular endothelial endothelial-mesenchymal transition (EndMT) was induced in male WT and YOD1 −/− mice by administration of Ang II (1 μg/kg per minute) via osmotic pump for four weeks. We showed a significantly increased expression of YOD1 in mouse vascular endothelial cells upon Ang II stimulation. Knockout of YOD1 resulted in a notable reduction in EndMT in vascular endothelial cells of Ang II-treated mouse; a similar result was observed in Ang II-treated human umbilical vein endothelial cells (HUVECs). We then conducted LC-MS/MS and co-immunoprecipitation (Co-IP) analyses to verify the binding between YOD1 and EndMT-related proteins, and found that YOD1 directly bound to β-catenin in HUVECs via its ovarian tumor-associated protease (OTU) domain, and histidine at 262 performing deubiquitination to maintain β-catenin protein stability by removing the K48 ubiquitin chain from β-catenin and preventing its proteasome degradation, thereby promoting EndMT of vascular endothelial cells. Oral administration of β-catenin inhibitor MSAB (20 mg/kg, every other day for four weeks) eliminated the protective effect of YOD1 deletion on vascular endothelial injury. In conclusion, we demonstrate a new YOD1-β-catenin axis in regulating Ang II-induced vascular endothelial injury and reveal YOD1 as a deubiquitinating enzyme for β-catenin, suggesting that targeting YOD1 holds promise as a potential therapeutic strategy for treating β-catenin-mediated vascular diseases.