| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | You, Shilong Xu, Jiaqi Yin, Zeyu Wu, Boquan Wang, Pengbo Hao, Mingjun Cheng, Cheng Liu, Mengke Zhao, Yuanhui Jia, Pengyu Jiang, Hongkun Li, Da Cao, Liu Zhang, Xingang Zhang, Ying Sun, Yingxian Zhang, Naijin |
| Abstract | Background Endothelial injury caused by Type 2 diabetes mellitus (T2DM) is considered as a mainstay in the pathophysiology of diabetic vascular complications (DVCs). However, the molecular mechanism of T2DM-induced endothelial injury remains largely unknown. Here, we found that endothelial WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) act as a novel regulator for T2DM-induced vascular endothelial injury through modulating ubiquitination and degradation of DEAD-box helicase 3 X-linked (DDX3X). Methods Single-cell transcriptome analysis was used to evaluate WWP2 expression in vascular endothelial cells of T2DM patients and healthy controls. Endothelial-specific Wwp2 knockout mice were used to investigate the effect of WWP2 on T2DM-induced vascular endothelial injury. In vitro loss- and gain-of-function studies were performed to assess the function of WWP2 on cell proliferation and apoptosis of human umbilical vein endothelial cells. The substrate protein of WWP2 was verified using mass spectrometry, coimmunoprecipitation assays and immunofluorescence assays. The mechanism of WWP2 regulation on substrate protein was investigated by pulse-chase assay and ubiquitination assay. Results The expression of WWP2 was significantly down-regulated in vascular endothelial cells during T2DM. Endothelial-specific Wwp2 knockout in mice significantly aggravated T2DM-induced vascular endothelial injury and vascular remodeling after endothelial injury. Our in vitro experiments showed that WWP2 protected against endothelial injury by promoting cell proliferation and inhibiting apoptosis in ECs. Mechanically, we found that WWP2 is down-regulated in high glucose and palmitic acid (HG/PA)-induced ECs due to c-Jun N-terminal kinase (JNK) activation, and uncovered that WWP2 suppresses HG/PA-induced endothelial injury by catalyzing K63-linked polyubiquitination of DDX3X and targeting it for proteasomal degradation. Conclusion Our studies revealed the key role of endothelial WWP2 and the fundamental importance of the JNK-WWP2-DDX3X regulatory axis in T2DM-induced vascular endothelial injury, suggesting that WWP2 may serve as a new therapeutic target for DVCs. |
| Related Links | https://cardiab.biomedcentral.com/counter/pdf/10.1186/s12933-023-01818-3.pdf |
| Ending Page | 23 |
| Page Count | 23 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| ISSN | 14752840 |
| DOI | 10.1186/s12933-023-01818-3 |
| Journal | Cardiovascular Diabetology |
| Issue Number | 1 |
| Volume Number | 22 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2023-05-06 |
| Access Restriction | Open |
| Subject Keyword | Diabetes Angiology Cardiology Type 2 diabetes mellitus Diabetic vascular complications Endothelial injury WWP2 DDX3X Ubiquitination |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cardiology and Cardiovascular Medicine Internal Medicine Endocrinology, Diabetes and Metabolism |
| Journal Impact Factor | 8.5/2023 |
| 5-Year Journal Impact Factor | 8.9/2023 |
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