2. Academic Validation
  3. Endothelial deubiquinatase YOD1 mediates Ang II-induced vascular endothelial-mesenchymal transition and remodeling by regulating β-catenin

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

  • Acta Pharmacol Sin. 2024 Apr 19. doi: 10.1038/s41401-024-01278-9.
Wan-Te Lin # 1 2,  Yu-Cheng Jiang # 2,  Yi-Lin Mei 2,  Yang-Hao Chen 1 2,  Zhao-Zheng Zheng 2,  Xue Han 2,  Gao-Jun Wu 1,  Wei-Jian Huang 3,  Bo-Zhi Ye 4 5,  Guang Liang 6 7 8
Affiliations

Affiliations

  • 1 Department of Cardiology and the Key Laboratory of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China.
  • 2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
  • 3 Department of Cardiology and the Key Laboratory of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China. weijianhuang69@126.com.
  • 4 Department of Cardiology and the Key Laboratory of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China. fredye2012@163.com.
  • 5 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 325035, China. fredye2012@163.com.
  • 6 Department of Cardiology and the Key Laboratory of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China. wzmcliangguang@163.com.
  • 7 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. wzmcliangguang@163.com.
  • 8 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 325035, China. wzmcliangguang@163.com.
  • # Contributed equally.
PMID: 38641745 DOI: 10.1038/s41401-024-01278-9
Abstract

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.

Keywords

YOD1; angiotensin II; deubiquitinating enzyme; endothelial-mesenchymal transition; vascular remodeling; β-catenin.

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