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

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.

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

“…These mechanisms are likely to be complementary, rather than mutually exclusive, all converging on one primary target, that is, IL‐1β, a major cytokine with a recognized role in the development of atherosclerosis and CV disease (Figure ). Finally, a glycaemia‐independent, molecule‐intrinsic, anti‐inflammatory mechanism has been proposed for canagliflozin and dapagliflozin, as has been shown in vitro in vascular endothelial cells and cardiofibroblast …”

“…Finally, a glycaemia-independent, molecule-intrinsic, anti-inflammatory mechanism has been proposed for canagliflozin and dapagliflozin, as has been shown in vitro in vascular endothelial cells and cardiofibroblast. 73…”

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

“…Through such a mechanism, agents that promote autophagy mitigate activation of the inflammasome . It is therefore noteworthy that the stimulation of autophagy by SGLT2 inhibitors is accompanied by a reduction in oxidative stress and normalization of mitochondrial structure and function, and this action is followed by effects to suppress inflammation, minimize coronary microvascular injury, enhance contractile performance and attenuate the development of cardiomyopathy …”

Canagliflozin, a sodium–glucose cotransporter 2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats

“…As the correlation between blood βOHB and renal NGAL expression was modest ( r = −0.41), mechanisms other than increased βOHB are possibly involved in renoprotection by canagliflozin with pre‐MI fasting. Activation of AMPK is one of the candidates, but the present results showed that the contribution of AMPK to renoprotection against diabetes mellitus‐induced worsening of CRS was limited. It has been suggested that the reduction of oxygen consumption in the proximal tubules and prevention of cellular senescence are the mechanisms of renoprotection by an SGLT2 inhibitor, but whether these mechanisms are involved in amelioration of CRS should be examined in future studies.…”