Effect of anti-hyperglycemic drugs on endoplasmic reticulum (ER) stress in human coronary artery endothelial cells.

Abstract Endoplasmic reticulum (ER) stress plays a critical role in progression of diabetes and development of complications, notably cardiovascular disease. Some of the contemporary anti-hyperglycemic drugs have been shown to inhibit ER stress. To extend these observations, the effects of various anti-hyperglycemic agents were screened for their effects on ER stress. Seven classes of anti-hyperglycemic drugs were screened including sulfonylureas, meglitinides, metformin, α glucosidase inhibitors, thiazolidinedione, glucagon like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors. ER stress was measured in human coronary artery endothelial cells (HCAEC) either treated with tunicamycin (TM) or cultured in hyperglycemic conditions (27.5 mM dextrose). The ER stress was measured with the secreted alkaline phosphatase (ES-TRAP) assay. Mediators of the unfolded protein response, including activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), phospho-inositol-requiring enzyme 1α (pIRE1α), IRE1α, phospho-protein kinase R (PKR)-like endoplasmic reticulum kinase (pPERK), and PERK were measured by Western blot. Metformin, GLP-1 receptor agonists (GLP-1, exendin 4, liraglutide, albiglutide, and lixisenatide) and SGLT-2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) were the only anti-hyperglycemic drugs screened that reduced ER stress caused by pharmacological (tunicamycin) or hyperglycemic conditions. High-dextrose and TM increased IRE1α and PERK phosphorylation and ATF6 and GRP78 expression, while treatment with metformin, liraglutide (a GLP-1 receptor agonist) and dapagliflozin (a SGLT-2 inhibitor), suppressed IRE1α and PERK phosphorylation as well as ATF6 and GRP78 expression. Thus, the cardioprotective effects of metformin, some of the GLP-1 receptor agonists and SGLT2 inhibitors may be partly related to their ability to reduce ER stress.