Sodium-glucose cotransporter 2 inhibitors antagonize lipotoxicity in human myeloid angiogenic cells and ADP-dependent activation in human platelets: potential relevance to prevention of cardiovascular events

• Published in: Cardiovascular diabetology Vol. 19; no. 1; pp. 46 - 15
• Main Authors: Spigoni, Valentina, Fantuzzi, Federica, Carubbi, Cecilia, Pozzi, Giulia, Masselli, Elena, Gobbi, Giuliana, Solini, Anna, Bonadonna, Riccardo C., Dei Cas, Alessandra
• Format: Journal Article
• Language: English
• Published: England BioMed Central 07.04.2020; BMC
• Subjects: Adenosine Diphosphate - pharmacology; Amiloride; Angiogenesis; Antidiabetics; Apoptosis; Apoptosis - drug effects; Arteriosclerosis; Atherosclerosis; Benzhydryl Compounds - pharmacology; Blood Platelets - drug effects; Blood Platelets - metabolism; Blood Platelets - pathology; Cell activation; Cell culture; Cells, Cultured; Cytometry; Diabetes; Diabetes mellitus (non-insulin dependent); Endothelial Progenitor Cells - drug effects; Endothelial Progenitor Cells - metabolism; Endothelial Progenitor Cells - pathology; Experiments; Gene expression; Glucosides - pharmacology; Heart failure; Humans; Inflammation Mediators - metabolism; Interleukin 1; Isoforms; Kidney diseases; Myeloid angiogenic cells; Na+/H+-exchanging ATPase; Original Investigation; Oxidants; Oxidative Stress - drug effects; PAC1 protein; Peripheral blood; Platelet Activation - drug effects; Platelets; SGLT-2 inhibitors; Signal Transduction; Sodium-glucose cotransporter; Sodium-Glucose Transporter 2 - metabolism; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Hydrogen Exchangers - metabolism; Sodium-proton exchanger; Stearic acid; Stearic Acids - toxicity; Superoxide dismutase; Thermal cycling; Thrombosis; Tumor necrosis factor-TNF; Tumor necrosis factor-α; United States > US; Italy; SGLT-2 inhibitors; Sodium-proton exchanger; Myeloid angiogenic cells; Platelets; Atherosclerosis
• ISSN: 1475-2840; 1475-2840
• DOI: 10.1186/s12933-020-01016-5

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. 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. MAC 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. NHE 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. EMPA 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.