glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

• Published in: Diabetologia 2010-10, Vol.53 (10), p.2256-2263
• Main Authors: Hattori, Y, Jojima, T, Tomizawa, A, Satoh, H, Hattori, S, Kasai, K, Hayashi, T
• Format: Article
• Language: English
• Subjects: Antibodies; Binding sites; Biological and medical sciences; Blotting, Western; Butter; Cardiovascular disease; Cells, Cultured; Cloning; Cytokines - genetics; Cytokines - metabolism; Diabetes. Impaired glucose tolerance; Dose-Response Relationship, Drug; Drug dosages; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; endothelial cells; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Enzymes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; GLP-1; Glucagon; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Humans; Kinases; Liraglutide; Medical sciences; NF-kappa B p50 Subunit - genetics; NF-kappa B p50 Subunit - metabolism; NF-κB; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide - genetics; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Peptides; Phosphorylation; Phosphorylation - drug effects; Proteins; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-010-1831-8

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 κB (NF-κB) 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-κB activation. We therefore examined the effect of liraglutide on TNFα-induced NF-κB activation and NF-κB-dependent expression of proinflammatory genes. Liraglutide dose-dependently inhibited NF-κB activation and TNFα-induced IκB degradation. It also reduced TNFα-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-κB 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-κB 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.