The role of endothelial ion channels in vascular protection By SGLT2 inhibitors and GLP1 receptor agonists

The primary aim of this thesis was to elucidate the potential mechanisms underlying the endothelial protective effects of sodium glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs), with a particular focus on endothelial ion channels and intracellular calcium homeostasis.
We first reviewed current knowledge on the expression and function of endothelial ion channels in heart failure, focusing on SGLT2i’s protective effects mediated through modulation of endothelial ion channels, and highlighted the role of NHE1 in SGLT2i-mediated mechanisms. Next, we investigated the mechanisms underlying the endothelial protective effects of SGLT2i empagliflozin (EMPA) in human coronary artery endothelial cells exposed to cyclic stretch as well as shear stress, and elucidated the potential involvement of endothelial NHE1 and NCX. Moreover, we performed a translational sub-study using blood samples from the open-label MERCURI-1 study, in which EMPA was administered to patients undergoing cardiac surgery during the perioperative period. We evaluated the potential effects of short-term EMPA treatment on surgery-induced changes in endothelial function, cardiac injury, as well as on endothelial permeability in vitro. Finally, we explored the effects of GLP-1RA semaglutide on intracellular Ca2+ overload and oxidative stress induced by disturbed flow, and assessed whether the underlying mechanisms are GLP-1R-dependent or not.
We found that semaglutide can inhibit endothelial NCX activity, suggesting that SGLT2i and GLP-1RAs may, to some extent, share common mechanisms in improving endothelial function. Therefore, further studies are warranted to investigate the effects of combining these drugs on endothelial protection and to elucidate the underlying mechanisms.