RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells
Open accessAbstract
Aims/hypothesis Glucagon-like peptide-1 (GLP-1), a member of the proglucagon-derived peptide family, was seen to exert favourable actions on cardiovascular function in preclinical and clinical studies. The mechanisms through which GLP-1 modulates cardiovascular function are complex and incompletely understood. We thus investigated whether the GLP-1 analogue, liraglutide, which is an acylated GLP-1, has protective effects on vascular endothelial cells.Methods Nitrite and nitrate were measured in medium with an automated nitric oxide detector. Endothelial nitric oxide synthase (eNOS) activation was assessed by evaluating the phosphorylation status of the enzyme and evaluating eNOS activity by citrulline synthesis. Nuclear factor kappaB (NF-kappaB) activation was assessed by reporter gene assay.Results Liraglutide dose-dependently increased nitric oxide production in HUVECs. It also caused eNOS phosphorylation, potentiated eNOS activity and restored the cytokine-induced downregulation of eNOS (also known as NOS3) mRNA levels, which is dependent on NF-kappaB activation. We therefore examined the effect of liraglutide on TNFalpha-induced NF-kappaB activation and NF-kappaB-dependent expression of proinflammatory genes. Liraglutide dose-dependently inhibited NF-kappaB activation and TNFalpha-induced IkappaB degradation. It also reduced TNFalpha-induced MCP-1 (also known as CCL2), VCAM1, ICAM1 and E-selectin mRNA expression. Liraglutide-induced enhancement of nitric oxide production and suppression of NF-kappaB activation were attenuated by the AMP-activated protein kinase (AMPK) inhibitor compound C or AMPK (also known as PRKAA1) small interfering RNA. Indeed, liraglutide induced phosphorylation of AMPK, which occurs through a signalling pathway independent of cyclic AMP.Conclusions/interpretation Liraglutide exerts an anti-inflammatory effect on vascular endothelial cells by increasing nitric oxide production and suppressing NF-kappaB activation, partly at least through AMPK activation. These effects may explain some of the observed vasoprotective properties of liraglutide, as well as its beneficial effects on the cardiovascular system.
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Restoring NF-κB activity reversed cytokine-induced reductions in eNOS (NOS3) mRNA levels.
“Restoring NF-κB activity reversed cytokine-induced reductions in eNOS (NOS3) mRNA levels.”
From Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications (2024) · cites this paper as [41]
The Results section (page unavailable) reports that inhibiting NF-κB partially prevented the TNFα-induced reduction in eNOS mRNA. It also reports that liraglutide attenuated that reduction; the paper says suppression, not restoration, of NF-κB activity accompanied this effect. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredLiraglutide (100 μM) reduced the mRNA expression of adhesion molecules such as VCAM-1, ICAM-1, and E-selectin in TNF-α- or LPS-stimulated human aortic endothelial cells and human umbilical vein endothelial cells.
“Liraglutide (100 μM) reduced the mRNA expression of adhesion molecules such as vascular cell adhesion molecule- (VCAM-) 1, ICAM-1, and E-selectin in TNF-α- or LPS-stimulated human aortic endothelial cells and human umbilical vein endothelial cells [60–62].”
From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [61]
The section on mRNA induction in HUVECs (Fig. 6a; page not provided) reports that liraglutide reduced TNF-α-induced VCAM1, ICAM1 and E-selectin mRNA expression. It reports a dose of 1 μg/ml, not 100 μM, and does not establish the stated result for LPS-stimulated cells or human aortic endothelial cells. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThere was a dose-response relationship between liraglutide and increased nitric oxide generation in HUVECs.
“There was a dose-response relationship between liraglutide and increased nitric oxide generation in.”
From Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications (2024) · cites this paper as [41]
Liraglutide induced eNOS phosphorylation and enhanced its activity in HUVECs.
“As a result of this factor, eNOS phosphorylation was also induced, and its activity was enhanced.”
From Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications (2024) · cites this paper as [41]
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- Authors
- Hattori, Y., Jojima, T., Tomizawa, A., Satoh, H., Hattori, S., Kasai, K., & Hayashi, T.
- Affiliations
- Dokkyo University (JP)
- Nagoya University (JP)
- Corresponding author
- Hattori, Y.
- Venue
- Diabetologia
- Published
- 2010-07-01
- Volume
- 53
- Issue
- 10
- Pages
- 2256-2263
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W1997332398
- Cited by
- 183
- References
- 26
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 6 · 2023: 3 · 2022: 10 · 2021: 11 · 2020: 8 · 2019: 11 · 2018: 12 · 2017: 9 · 2016: 13 · 2015: 19 · 2014: 20 · 2013: 22 · 2012: 16
- FWCI
- 11.70
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2011-12-15)
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Private School Promotion Foundation
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- liraglutide, glucagon-like peptide-1 analogues, nitric oxide production, endothelial nitric oxide synthase, NF-κB activation, AMPK, anti-inflammatory activity, vascular endothelial cells, TNF-α, pro-inflammatory gene expression, cardioprotection, retracted article
- MeSH terms
- Liraglutide, Cells, Cultured, Dose-Response Relationship, Drug, Endothelium, Vascular, Humans, Nitric Oxide, Phosphorylation, Blotting, Western, Cytokines, Reverse Transcriptase Polymerase Chain Reaction, Endothelial Cells, NF-kappa B p50 Subunit, Glucagon-Like Peptide 1, Nitric Oxide Synthase Type III
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