Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms

Mancini, Sarah J.; Boyd, Daria; Katwan, Omar J.; Strembitska, Anastasiya; Almabrouk, Tarek A.; Kennedy, Simon; Palmer, Timothy M.; Salt, Ian P.

Abstract

Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling.

Citation

Mancini, S. J., Boyd, D., Katwan, O. J., Strembitska, A., Almabrouk, T. A., Kennedy, S., Palmer, T. M., & Salt, I. P. (2018). Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Scientific reports, 8(1), Article 5276. https://doi.org/10.1038/s41598-018-23420-4

• Journal Article Type: Article
• Acceptance Date: Mar 12, 2018
• Online Publication Date: Mar 27, 2018
• Publication Date: Dec 1, 2018
• Deposit Date: Oct 30, 2018
• Publicly Available Date: Oct 30, 2018
• Journal: Scientific Reports
• Print ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 1
• Article Number: 5276
• DOI: https://doi.org/10.1038/s41598-018-23420-4
• Public URL: https://hull-repository.worktribe.com/output/1136962
• Publisher URL: https://www.nature.com/articles/s41598-018-23420-4#article-info
• Contract Date: Oct 30, 2018