2. Academic Validation
  3. Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X

Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X

  • Cardiovasc Diabetol. 2023 May 6;22(1):107. doi: 10.1186/s12933-023-01818-3.
Shilong You # 1,  Jiaqi Xu # 1,  Zeyu Yin 1,  Boquan Wu 1,  Pengbo Wang 1,  Mingjun Hao 2,  Cheng Cheng 1,  Mengke Liu 1,  Yuanhui Zhao 1,  Pengyu Jia 1,  Hongkun Jiang 3,  Da Li 2 4,  Liu Cao 5 6,  Xingang Zhang 7,  Ying Zhang 8 9,  Yingxian Sun 10 11,  Naijin Zhang 12 13
Affiliations

Affiliations

  • 1 Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China.
  • 2 Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
  • 3 Department of Pediatrics, The First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, China.
  • 4 Key Laboratory of Reproductive and Genetic Medicine (China Medical University), National Health Commission, Shenyang, 110004, China.
  • 5 Key Laboratory of Medical Cell Biology, Ministry of Education, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China.
  • 6 Institute of School of Basic Medicine, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China.
  • 7 Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China. zhangxingang80@aliyun.com.
  • 8 Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China. yzhang02@cmu.edu.cn.
  • 9 Institute of School of Basic Medicine, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China. yzhang02@cmu.edu.cn.
  • 10 Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China. yxsun@cmu.edu.cn.
  • 11 Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China. yxsun@cmu.edu.cn.
  • 12 Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China. njzhang@cmu.edu.cn.
  • 13 Key Laboratory of Reproductive and Genetic Medicine (China Medical University), National Health Commission, Shenyang, 110004, China. njzhang@cmu.edu.cn.
  • # Contributed equally.
PMID: 37149668 DOI: 10.1186/s12933-023-01818-3
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.

Keywords

DDX3X; Diabetic vascular complications; Endothelial injury; Type 2 diabetes mellitus; Ubiquitination; WWP2.

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