Sitagliptin protects against hypoxia/reoxygenation (H/R)-induced cardiac microvascular endothelial cell injury

Inhibition of hypoxia/reoxygenation (H/R)-induced insult in cardiac microvascular endothelial cells (CMECs) has been considered as a promising therapeutic strategy for the treatment of ischemic cardiovascular disease. In the present study, we found that H/R significantly increased the expression of dipeptidyl peptidase (DPP)-4 in CMECs. Treatment with the DPP-4 inhibitor sitagliptin, a licensed drug used for the treatment of type 2 diabetes mellitus (T2DM), ameliorated H/R-induced oxidative stress by decreasing the expression of NOX-4 and restoring the intracellular level of GSH in CMECs. Sitagliptin could also improve H/R-induced mitochondrial dysfunction by increasing intracellular MMP and ATP. Additionally, we found that the presence of sitagliptin prevented H/R-induced reduced cell viability and LDH release. Notably, our findings indicate that sitagliptin possesses an anti-inflammatory effect against H/R-induced expression of IL-6, IL-8, and TNF-α as well as secretion of HMGB1. Mechanistically, we found that sitagliptin suppresses activation of p38/NF-κB signaling. These findings suggest that sitagliptin may have potential as a therapeutic agent for the treatment of cardiovascular diseases.