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Abstract
BackgroundThe clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated. We tested the effects of SGLT2i on inflammation and oxidant stress in a model of stearic acid (SA)-induced lipotoxicity in MAC and on PLT activation. The possible involvement of the Na+/H+ exchanger (NHE) was also explored.MethodMAC and PLT were isolated from peripheral blood of healthy subjects and incubated with/without SGLT2i [empagliflozin (EMPA) and dapagliflozin (DAPA) 1–100 μM] to assess their effects on SA (100 μM)-induced readouts of inflammation, oxidant stress and apoptosis in MAC and on expression of PLT activation markers by flow-cytometry after ADP-stimulation. Potential NHE involvement was tested with amiloride (aspecific NHE inhibitor) or cariporide (NHE1 inhibitor). Differences among culture conditions were identified using one-way ANOVA or Friedman test.ResultsNHE isoforms (1,5–9), but not SGLT2 expression, were expressed in MAC and PLT. EMPA and DAPA (100 μM) significantly reduced SA-induced inflammation (IL1β, TNFα, MCP1), oxidant stress (SOD2, TXN, HO1), but not apoptosis in MAC. EMPA and DAPA (both 1 μM) reduced PLT activation (CD62p and PAC1 expression). SGLT2i effects were mimicked by amiloride, and only partially by cariporide, in MAC, and by both inhibitors in PLT.ConclusionsEMPA and DAPA ameliorated lipotoxic damage in stearate-treated MAC, and reduced ADP-stimulated PLT activation, potentially via NHE-inhibition, thereby pointing to plaque stabilization and/or thrombosis inhibition as potential mechanism(s) involved in SGLT2i-mediated cardiovascular protection.
Highlights
The clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated
Cardiovascular outcome trials (CVOT) [1,2,3], conducted at almost glucose equipoise in patients with type 2 diabetes mellitus (T2D), have shown that, in patients with established atherosclerotic cardiovascular disease (ASCVD), but not in patients with multiple risk factors (MRF), SGLT2i as a whole reduce the risk of major adverse cardiovascular events (MACE), suggesting a class effect [4]
Effects of SGLT2i on stearic acid (SA)‐induced inflammation, oxidant stress and apoptosis in MAC Pilot experiments excluded any cytotoxic effect of SGLT2i in MAC
Summary
The clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated. According to recently reported evidence in cardiomyocytes, SGLT2i can inhibit N a+/H+ exchanger (NHE), resulting into a fall in intracellular Na+ and Ca2+ while increasing mitochondrial Ca2+ concentrations, optimizing cardiac mitochondrial function and energetics [8] This off-target effect of SGLT2i may explain, at least in part, the beneficial influence of SGLT2i treatment on heart failure [4, 6]. On-target effects of SGLT2i, which reduce the burden of the hyperfiltrating glomerulus, and/or off-target effects again through NHE inhibition in renal tubular cells may help to explain the benefits exerted by SGLT2i on CKD [4, 5] None of these lines of evidence can account for the reduction in MACE brought about by SGLT2i in patients with established ASCVD [4, 5]
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