Endothelial deubiquinatase YOD1 mediates AngⅡ-induced vascular endothelial-mesenchymal transition and remodeling by regulatingβ-catenin  

作　　者：Wan-te Lin Yu-cheng Jiang Yi-lin Mei Yang-hao Chen Zhao-zheng Zheng Xue Han Gao-jun Wu Wei-jian Huang Bo-zhi Ye Guang Liang 

机构地区：[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]School of Pharmaceutical Sciences,Hangzhou Medical College,Hangzhou,325035,China

出　　处：《Acta Pharmacologica Sinica》2024年第8期1618-1631,共14页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82271347 to GJW);the Major project of Wenzhou Science and Technology Bureau(ZY2020016 to GJW).

摘　　要：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(1μg/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 toβ-catenin in HUVECs via its ovarian tumor-associated protease(OTU)domain,and histidine at 262 performing deubiquitination to maintainβ-catenin protein stability by removing the K48 ubiquitin chain fromβ-catenin and preventing its proteasome degradation,thereby promoting EndMT of vascular endothelial cells.Oral administration ofβ-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 forβ-catenin,suggesting that targeting YOD1 holds promise as a potential therapeutic strategy for treatingβ-catenin-mediated vascular diseases.

关 键 词：YOD1 vascular remodeling Β-CATENIN endothelial-mesenchymal transition deubiquitinating enzyme angiotensinⅡ 

分 类 号：R54[医药卫生—心血管疾病]