Metabolic syndrome (MetS) is a complex medical disorder characterized by
insulin resistance,
hypertension, and high risk of
coronary disease and
stroke.
Microvascular rarefaction and endothelial dysfunction have also been linked with MetS, and recent evidence from clinical studies supports the efficacy of
incretin-based
antidiabetic therapies for vascular protection in diabetes. Previous studies pointed out the importance of dipeptidyl peptidase-4 (DPP-4) inhibition in endothelial cells due to getting protection against metabolic pathologies. We therefore aimed to investigate the acute effects of a
DPP-4 inhibitor,
sitagliptin, on vascular function in rats with high-
sucrose diet-induced MetS. In order to elucidate the mechanisms implicated in the effects of DPP-4 inhibition, we tested the involvement of NO pathway and epigenetic regulation in the MetS. Acute use of
sitagliptin protects the vascular function in the rats with MetS in part due to NO pathway via restoring the depressed aortic relaxation responses mediated by receptors. Application of
sitagliptin enhanced the depressed phosphorylation levels of both the endothelial
NO synthase and the apoptotic status of
protein kinase B, known as Akt, in endothelium-intact thoracic aorta from rats with MetS. One-hour application of
sitagliptin on aortic rings from rats with MetS also induced remarkable histon posttranslational modifications such as increased expression of H3K27Me3, but not of H3K27Me2, resulting in an accumulation of the H3K27Me3. Our findings suggest that, in addition to its well-known
hypoglycemic action,
sitagliptin may also have beneficial effects on
hyperglycemia-induced vascular changes in an endotheium-dependent manner. These present results with
sitagliptin aside from the glycaemic control, may demonstrate its important role in the treatment of patients with MetS.