ArticleCardiovascular diabetology2023
Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X.
Article in Cardiovascular diabetology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 25 citations in OpenAlex.
- Targeted activation of PPARG or AKT1 alleviates liver injury in mice with type 2 diabetes and sepsis by modulating inflammatory and metabolic pathways.Annals of medicine · 2026Article
- E3 ubiquitin ligase SYVN1 mediates K63-linked ubiquitination of DDX3X to activate Macrophage NLRP3 Inflammasome.bioRxiv : the preprint server for biology · 2026Article
- Endothelial dysfunction in human diabetic vascular complications: translating single-cell transcriptomics into therapeutic opportunities.Molecular medicine (Cambridge, Mass.) · 2026Review
- Article
- Regulation of Mitophagy by Low-Intensity Pulsed Ultrasound Attenuates Endothelial Dysfunction.Metabolites · 2026Article
- DDX3X induces mesenchymal transition of endothelial cells by disrupting BMPR2 signaling.FEBS open bio · 2026Article
- WWP2 underlies ROS-induced granulosa cell apoptosis by promoting ubiquitination of BAK in polycystic ovary syndrome.Cell death & disease · 2026Article
- E3 ubiquitin ligase trim36 targets ddx3x for degradation to reprogram macrophage polarization and ameliorate tubal factor infertility in rats.Cell biology and toxicology · 2026Article
- Ubiquitination modifications as central regulators of metabolic dysfunction in type 2 diabetes mellitus.Frontiers in endocrinology · 2026Review
- Methylation of DPP9 regulates immune surveillance in non-small cell lung cancer by promoting macrophage ferroptosis via WWP2 ubiquitination.American journal of cancer research · 2026Article
- Enhanced WWP2 Exacerbates Podocyte Injury in Lupus Nephritis through Monoubiquitylating H2A at K119.International journal of biological sciences · 2026Article
- Structural and functional perspectives on DEAD-box RNA helicases in the rubber tree cold stress response.Frontiers in plant science · 2026Review
- WWP2 in immune surveillance and antigen presentation: context-dependent roles in B cells, T cells, and tumor immune escape.Frontiers in immunology · 2026Review
- The role of NEDD4-mediated ubiquitination of AQP5 in allergic rhinitis: implications for nasal mucosal barrier function.Frontiers in immunology · 2026Article
- Multi-omics integrated analysis identifies causal risk factors and therapeutic targets for diabetic retinopathy.Journal of translational medicine · 2025Article
- Targeting FAM134B-DDX3X axis inhibiting AKT signaling in hepatocellular carcinoma.Cell death & disease · 2025Article
- Snijders Blok-Campeau Syndrome Associated with Pulmonary Arterial Hypertension: A Case Report.Reports (MDPI) · 2025Article
- Static training improves insulin resistance in skeletal muscle of type 2 diabetic mice via the IGF-2/IGF-1R pathway.Scientific reports · 2025Article
- New insights into the role of ubiquitination in angiogenesis (Review).International journal of molecular medicine · 2025Review
- Aberrant STING activation promotes macrophage senescence by suppressing autophagy in vascular aging from diabetes.iScience · 2025Article
Corrections and comments
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Authors and funding
17 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundEndothelial 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).
methodsSingle-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.
resultsThe 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.
conclusionOur 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.
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