Dipeptidyl peptidase-4 inhibition prevents vascular dysfunction induced by β-adrenergic hyperactivity

Chronic stimulation of the β-adrenergic sympathetic system induces vascular dysfunction which is associated with increased inflammatory cytokines production. A recently proposed therapy to control vascular injury through inflammatory processes involves inhibition of the enzyme dipeptidyl peptidase-IV (DPP4). The present study investigates whether the inhibition of DPP4 prevents the increase in inflammatory markers induced by isoproterenol and restores endothelial function in vivo and in vitro. Male Wistar rats were divided into four groups: vehicle (VHC), an isoproterenol-treated group (ISO), a sitagliptin-treated group (SITA), and an isoproterenol and sitagliptin-treated group (ISO + SITA). The ISO group exhibited significantly increased contractile responses to phenylephrine associated with reduced endothelial participation, which was totally prevented by DPP4 inhibition. In vitro incubation with isoproterenol had no effect on vascular smooth muscle cells, however isoproterenol increased the activity of DPP4 and the expression of inflammatory cytokines in endothelial cells, while sitagliptin reduced the level of cytokines to basal level. In conclusion, we have shown that beta-adrenergic receptor activation can increase DPP4 activity, which was associated with vascular dysfunction and cytokine expression in endothelial cells. The important role of DPP4 was further supported by sitagliptin, which reversed vascular changes induced by isoproterenol in vivo and in vitro.