SAT-LB013 The Effect of Select GLP1 Agonists and SGLT2 Inhibitors on the Unfolded Protein Response in Primary Human Coronary Artery Endothelial Cells

Abstract

Background. GLP1R agonists and SGLT2 inhibitors are classes of medications used in diabetes management. They possess antioxidative properties and inhibit the unfolded protein response (UPR) (endoplasmic reticulum (ER) stress). Since the UPR is involved in atherogenesis, we examined the effects of the GLP1R agonists GLP1, exendin 4, liraglutide, albiglutide, and lixisenatide and the SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin on ER stress in primary human coronary artery endothelial cells (HCAEC). Methods. ER stress was measured in HCAEC treated with either tunicamycin (TM) or high-dextrose using the ER stress secreted alkaline phosphatase (ES-TRAP) assay. Activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), inositol-requiring enzyme 1α (IRE1α), phospho-IRE1α, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and phospho-PERK were measured by Western blot. Results. Treatment with tunicamycin (TM) and high-dextrose increased ER stress in HCAEC. Treatment of cells exposed to TM or high-dextrose with the GLP1R agonists GLP1, exendin 4, liraglutide, albiglutide, and lixisenatide resulted in a dose-dependent decrease in ER stress. Likewise, treatment with canagliflozin, dapagliflozin, and empagliflozin inhibited ER stress. High-dextrose and TM increased IRE1α and PERK phosphorylation and ATF6 and GRP78 expression. However, treatment with liraglutide (a GLP1R agonist) and dapagliflozin (a SGLT2 inhibitor), suppressed IRE1α and PERK phosphorylation as well as ATF6 and GRP78 expression. Discussion. Treatment with select GLP1R agonists and SGLT2 inhibitors suppressed the UPR and subsequent ER stress. Conclusions. Our results suggest that GLP1R agonists and SGLT2 inhibitors may promote cardiovascular health by targeting coronary artery endothelial cells. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.