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

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.

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