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Canagliflozin inhibits interleukin-1?-stimulated cytokine and chemokine secretion
in vascular endothelial cells by AMP-activated protein kinase-dependent and
-independent mechanisms
#MMPMID29588466
Mancini SJ
; Boyd D
; Katwan OJ
; Strembitska A
; Almabrouk TA
; Kennedy S
; Palmer TM
; Salt IP
Sci Rep
2018[Mar]; 8
(1
): 5276
PMID29588466
show ga
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-1?-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-1?-stimulated cell surface levels of adhesion molecules or
nuclear factor-?B signalling. Despite these identical effects of canagliflozin
and A769662, IL-1?-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but
not A769662, whereas IL-1?-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-1? signalling.
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