温州医科大学梁广团队取得一项新突破。他们的最新研究探明了，内皮去泛素酶YOD1通过调节β-连环蛋白介导Ang II诱导的血管内皮-间质转化和重塑。这一研究成果发表在2024年4月19日出版的国际学术期刊《中国药理学报》上。

研究人员表示，高血压是引起血管损伤的重要因素。去泛素酶参与高血压引起的血管损伤的调节。

在本研究中，该课题组研究人员探讨了去泛素酶YOD1在高血压引起的血管损伤中的具体作用。通过渗透泵给药(1 μg/kg/min) 4周，可诱导雄性WT和YOD1^-/-小鼠血管内皮-间充质转化(EndMT)。研究小组发现，在Ang II刺激下，小鼠血管内皮细胞中YOD1的表达显著增加。敲除YOD1导致在Ang II处理的小鼠血管内皮细胞中EndMT显著降低；在Ang II处理的人脐静脉内皮细胞(HUVECs)中也观察到类似的结果。

随后，研究人员通过LC-MS/MS和共免疫沉淀(Co-IP)分析验证了YOD1与EndMT相关蛋白的结合，发现YOD1通过其卵巢肿瘤相关蛋白酶(OTU)结构域直接与HUVECs中的β-catenin结合，262位点的组氨酸通过去除β-catenin上的K48泛素链，阻止其蛋白酶体降解，从而维持β-catenin蛋白的稳定性，从而促进血管内皮细胞的EndMT。口服β-catenin抑制剂MSAB (20mg/kg，每隔一天，连续4周)消除了YOD1缺失对血管内皮损伤的保护作用。

总之，小组发现了一个新的在调节Ang II诱导的血管内皮损伤中的YOD1-β-catenin轴，并揭示了YOD1是β-catenin的去泛素化酶，这表明靶向YOD1有望成为治疗β-catenin介导的血管疾病的潜在治疗策略。

附：英文原文

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

Author: 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

Issue&Volume: 2024-04-19

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 (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 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 (20mg/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.

DOI: 10.1038/s41401-024-01278-9

Source: https://www.nature.com/articles/s41401-024-01278-9