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Background: In diabetes, endothelial dysfunction leads to vascular complications that negatively impact on patient outcome. Endothelial dysfunction may be mediated by hyperglycemia-induced oxidative stress, protein kinase C-β (PKC-β) activation and endoplasmic reticulum (ER) stress. As these events are antagonized by glucagon-like peptide-1 (GLP-1), a therapeutic strategy able to increase GLP-1 levels may prevent endothelial impairment, providing a clinical benefit to diabetic patients. Aim of the present study was to test the capacity of dipeptidyl peptidase-4 (DPP-4) inhibitors, known to increase GLP-1 levels, to contrast hyperglycemia-induced effects in human umbilical vein endothelial cells (HUVECs). Methods: HUVECs grown for 21 days under conditions of continuous normal or high glucose (NG and HG, respectively) were treated with the DDP-4 inhibitors vildagliptin and sitagliptin (5 nM), or with GLP-1 (50 nM, as control) for 1 h. After cell harvesting, the following markers were quantitated: reactive oxygen species (ROS), thioredoxin-interacting protein (TXNIP) mRNA and PKC-β mRNA (oxidative stress); BAX and BCL-2 transcripts (apoptosis); BIP, CHOP and IRE-10 mRNA (ER stress) and GLP-1 receptor (GLP-1R). Results: In our experimental model, compared to NG, HG confirmed to trigger a significant increase of oxidative stress, apoptosis and ER stress while reducing GLP-1R expression. Under NG conditions, no treatment exerted any effect. In contrast, when HUVECs grown under HG conditions were treated with DDP-4 inhibitors, a significant overall improvement was observed in terms of oxidative and ER stress and apoptosis reduction. Notably, vildagliptin's activity was slightly better than sitagliptin's and both exerted effects comparable to that of GLP-1. Conclusions: DDP-4 inhibition by vildagliptin and sitagliptin had a protective action, similar to that of GLP-1, on HUVECs against HG-induced effects. Our preliminary findings suggest that, in diabetic patients, this strategy might be beneficial in contrasting endothelial dysfunction.

In Vitro Study Examining the Activity of Vildagliptin and Sitagliptin against Hyperglycemia-Induced Effects in Human Umbilical Vein Endothelial Cells