Effects of anagliptin on the stress induced accelerated senescence of human umbilical vein endothelial cells

Background: Dipeptidyl peptidase 4 (DPP-4) inhibitors have been used to treat type 2 diabetes mellitus (T2DM) via inhibition of the enzymatic activity of DPP-4 in degrading active circulating glucagon-like peptide-1. In addition to their glucose-lowering effect, DPP-4 inhibitors have pleiotropic effects. Cellular senescence regarded as important pathophysiological mechanism underlying many degenerative diseases, including atherosclerosis. This study was performed to examine whether the DPP-4 inhibitor, anagliptin, can directly protect against stress-induced accelerated senescence (SIAS) of vascular endothelial cells, regardless of changes in ambient glucose level. Methods: Cultured human umbilical vein endothelial cells (HUVECs) were exposed to various concentrations of H2O2, and a fixed high concentration of glucose (25 mM) with varying concentrations of palmitate. Changes in cell viability, senescence-associated beta-galactosidase (SA-beta-Gal), p16 protein, markers of endoplasmic reticulum (ER) stress, NOX4, NLRP inflammasome, lactate dehydrogenase (LDH) release and interleukin (IL) 1 beta levels were measured by Cell Counting Kit-8 assay, immunofluorescent staining, Western blotting, and enzyme- linked immunosorbent assay, respectively before and after application of anagliptin. Results: The application of oxidative and glucolipotoxic stresses markedly increased the degree of SIAS of HUVECs, represented by increased SA-beta-Gal immunopositivity and p16 protein expression. Aggravation of ER stress and inflammatory response were also observed through increased levels of ATF4, CHOP, peIF2 alpha, NOX4, NLRP inflammasome, LDH, and IL1 beta. These changes were markedly reversed by the administration of anagliptin. Conclusions: The DPP-4 inhibitor anagliptin effectively protects HUVECs against SIAS, suggesting its potential use in the development of new treatment strategies for aging.

Automated summary

The DPP-4 inhibitor anagliptin was found to protect vascular endothelial cells from stress-induced accelerated senescence, reducing markers of aging and alleviating cellular stress responses.