DPP-4 inhibitor saxagliptin ameliorates oxygen deprivation/reoxygenation-induced brain endothelial injury.

Abstract

Cardiovascular diseases are the main cause of death and disability among diabetes patients. Atherosclerosis-associated stroke is one of the most severe complications in diabetes patients. DPP-4 inhibitors are a class of potent anti-glycemic agents used to treat diabetes. Recently, some DPP-4 inhibitors have been shown to have cardiovascular benefits. In this study, we reveal that saxagliptin, one of the most widely used DPP-4 inhibitors, exhibits vascular protective effects against oxygen and glucose depletion/reoxygenation (OGD/R) in human brain vascular endothelial cells. Our data show that DPP-4 is fairly expressed in brain endothelial cells and its expression is induced by OGD/R. The results of MTT assay show that inhibition of DPP-4 by saxagliptin ameliorates OGD/R-induced reduced cell viability, and LDH assay demonstrated that saxagliptin reduces cellular toxicity. Furthermore, we show that saxagliptin mitigates OGD/R-induced collapse of mitochondrial membrane potential (MMP). Saxagliptin also reduces oxidative stress-induced release of 4-HNE and the NAPDH oxidase catalytic subunit NOX-4. At the molecular level, saxagliptin suppresses OGD/R-induced expression of pro-inflammatory cytokines and production of vascular adhesion molecules including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, monocyte chemoattractant protein 1 (MCP-1), vascular cellular adhesion molecule 1 (VCAM-1), and E-selectin. Mechanistically, saxagliptin inhibits activation of the NF-κB pathway by OGD/R via its inhibitory effect on nuclear p65 and NF-κB promoter activity. Collectively, our study explicitly demonstrates the cellular protective effect of saxagliptin against OGD/R-induced brain endothelial injury. Our findings extend our recognition of the protective roles of DPP-4 inhibitors in brain vascular cells.