ArticleArteriosclerosis, thrombosis, and vascular biology2016
Endothelial Dysfunction in Human Diabetes Is Mediated by Wnt5a-JNK Signaling.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed, 116 citations in OpenAlex.
- Endothelial dysfunction in human diabetic vascular complications: translating single-cell transcriptomics into therapeutic opportunities.Molecular medicine (Cambridge, Mass.) · 2026Review
- Sappanone A exerted promising therapeutic effects in vitiligo through Wnt5a-mediated noncanonical Wnt signaling.Journal of natural medicines · 2026Article
- Article
- Tiki2 restrains Wnt5a/Ror signaling to limit inflammation in acute kidney injury.Communications biology · 2026Article
- The effect of dapagliflozin on cardiorespiratory fitness in patients with coronary heart disease and type 2 diabetes mellitus following PCI: a single-center prospective randomized controlled study.BMC cardiovascular disorders · 2026Article
- Bioconverted Blueberry Extract Potentiates the Angiogenic and Endothelial Functions in Human Dermal Microvascular Endothelial Cells Under Oxidative Stress.Current issues in molecular biology · 2026Article
- The Association of Diabetes and Atherosclerosis: Understanding the Molecular Mechanism of the Double Burden.Current medicinal chemistry · 2026Review
- Role of Matricellular Proteins in Endothelial Cell Inflammation and Atherosclerosis.Antioxidants (Basel, Switzerland) · 2025Review
- Association of Serum Secreted Frizzled-Related Protein 5 Levels With Coronary Artery Disease.Cureus · 2025Article
- Wnt Signaling in Atherosclerosis: Mechanisms to Therapeutic Implications.Biomedicines · 2024Review
- TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production.International journal of biological sciences · 2024Article
- Downregulated calmodulin expression contributes to endothelial cell impairment in diabetes.Acta pharmacologica Sinica · 2023Article
- Effect of metformin on Wnt5a in individuals new-onset type 2 diabetes with different body mass indexes: The evidences from the real word research.Journal of diabetes and metabolic disorders · 2023Article
- Endothelial Dysfunction in Cardiorenal Conditions: Implications of Endothelial Glucocorticoid Receptor-Wnt Signaling.International journal of molecular sciences · 2023Review
- Distinctive Signs of Disease as Deterrents for the Endothelial Function: A Systematic Review.Metabolites · 2023Review
- Disturbed flow increases endothelial inflammation and permeability via a Frizzled-4-β-catenin-dependent pathway.Journal of cell science · 2023Article
- WNT5A, β‑catenin and SUFU expression patterns, and the significance of microRNA deregulation in placentas with intrauterine growth restriction.Molecular medicine reports · 2023Article
- Article
- Non-canonical WNT signalling in cardiovascular disease: mechanisms and therapeutic implications.Nature reviews. Cardiology · 2022Review
- Endothelium-Derived Relaxing Factors and Endothelial Function: A Systematic Review.Biomedicines · 2022Review
8 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
Abstract
objectiveEndothelial dysfunction is linked to insulin resistance, inflammatory activation, and increased cardiovascular risk in diabetes mellitus; however, the mechanisms remain incompletely understood. Recent studies have identified proinflammatory signaling of wingless-type family member (Wnt) 5a through c-jun N-terminal kinase (JNK) as a regulator of metabolic dysfunction with potential relevance to vascular function. We sought to gain evidence that increased activation of Wnt5a-JNK signaling contributes to impaired endothelial function in patients with diabetes mellitus. APPROACH AND
resultsWe measured flow-mediated dilation of the brachial artery and characterized freshly isolated endothelial cells by protein expression, eNOS activation, and nitric oxide production in 85 subjects with type 2 diabetes mellitus (n=42) and age- and sex-matched nondiabetic controls (n=43) and in human aortic endothelial cells treated with Wnt5a. Endothelial cells from patients with diabetes mellitus displayed 1.3-fold higher Wnt5a levels (P=0.01) along with 1.4-fold higher JNK activation (P<0.01) without a difference in total JNK levels. Higher JNK activation was associated with lower flow-mediated dilation, consistent with endothelial dysfunction (r=0.53, P=0.02). Inhibition of Wnt5a and JNK signaling restored insulin and A23187-mediated eNOS activation and improved nitric oxide production in endothelial cells from patients with diabetes mellitus. In endothelial cells from nondiabetic controls, rWnt5a treatment inhibited eNOS activation replicating the diabetic endothelial phenotype. In human aortic endothelial cells, Wnt5a-induced impairment of eNOS activation and nitric oxide production was reversed by Wnt5a and JNK inhibition.
conclusionsOur findings demonstrate that noncanonical Wnt5a signaling and JNK activity contribute to vascular insulin resistance and endothelial dysfunction and may represent a novel therapeutic opportunity to protect the vasculature in patients with diabetes mellitus.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.