Endothelial deubiquinatase YOD1 mediates Ang II-induced vascular endothelial-mesenchymal transition and remodeling by regulating ß-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 ß-catenin in HUVECs via its ovarian tumor-associated protease (OTU) domain, and histidine at 262 performing deubiquitination to maintain ß-catenin protein stability by removing the K48 ubiquitin chain from ß-catenin and preventing its proteasome degradation, thereby promoting EndMT of vascular endothelial cells. Oral administration of ß-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-ß-catenin axis in regulating Ang II-induced vascular endothelial injury and reveal YOD1 as a deubiquitinating enzyme for ß-catenin, suggesting that targeting YOD1 holds promise as a potential therapeutic strategy for treating ß-catenin-mediated vascular diseases.

Association between 1 Homozygous Deletion and Risk of Pancreatic Cancer: A Meta Analysis / 中国医学科学杂志(英文版)

Objective To clarify the possible association of 1 homozygous deletion with the susceptibility to pancreatic cancer. Methods We searched PubMed database, Chinese Journal Full Text Database (CNKI), and EMBASE to find the eligible studies published up to April 18, 2018 for evaluating the relationship between 1 homozygous deletion and pancreatic cancer. The frequency of null genotype for 1 between the pancreatic cancer group and the healthy control group was compared with - test, and odds ratios (s) value and 95% confidence interval (95% ) were calculated. Results A total of 9 studies met the inclusion criteria, and 5952 cases consisting of 2387 pancreatic cancer patients and 3565 healthy controls were included in the meta analysis. Compared with the control group, frequency of null genotype for 1 in the pancreatic cancer group was higher (33.4% . 38.7%, = 1.26, 95% = 1.01-1.58, = 0.04). Conclusion 1 homozygous deletion individuals may have higher susceptibility to pancreatic cancer.