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

Acta Pharmacologica Sinica (2024)Cite this article

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.

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Fig. 1: YOD1 is upregulated in Ang II-induced vascular endothelial injury.
Fig. 2: Knockout of YOD1 alleviated Ang II-induced vascular remodeling in vivo.
Fig. 3: Silencing YOD1 alleviated Ang II-induced endothelial EndMT in HUVECs.
Fig. 4: YOD1 directly interacts with β-catenin.
Fig. 5: YOD1 regulates the stability of β-catenin protein through deubiquitination.
Fig. 6: MSAB effectively blocks YOD1-mediated vascular endothelial injury and vascular remodeling in vivo.
Fig. 7: G5 alleviated Ang II-mediated vascular remodeling in mice.
Fig. 8: Schematic illustration of the main finding in this study.

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Acknowledgements

We are grateful to Meng-xin Zhang, Wen-ting Wang and Jian-song Lin from the Scientific Research Center of Wenzhou Medical University for their help in immunofluorescence experiment. This study was supported by the National Natural Science Foundation of China (82271347 to GJW) and the Major project of Wenzhou Science and Technology Bureau (ZY2020016 to GJW).

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  1. These authors contributed equally: Wan-te Lin, Yu-cheng Jiang

Authors and Affiliations

  1. Department of Cardiology and the Key Laboratory of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China

    Wan-te Lin, Yang-hao Chen, Gao-jun Wu, Wei-jian Huang, Bo-zhi Ye & Guang Liang

  2. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China

    Wan-te Lin, Yu-cheng Jiang, Yi-lin Mei, Yang-hao Chen, Zhao-zheng Zheng, Xue Han & Guang Liang

  3. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 325035, China

    Bo-zhi Ye & Guang Liang

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Contributions

GL, WJH, and BZY contributed to the literature search and study design. WTL, YCJ, YLM, YHC, ZZZ, XH carried out the experiments. BZY contributed to data collection and analysis. WTL, BZY, and GJW participated in the drafting of the article. GL and WJH revised the manuscript.

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Correspondence to Wei-jian Huang, Bo-zhi Ye or Guang Liang.

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Lin, Wt., Jiang, Yc., Mei, Yl. et al. Endothelial deubiquinatase YOD1 mediates Ang II-induced vascular endothelial-mesenchymal transition and remodeling by regulating β-catenin. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01278-9

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