A inibição da DPP-4 previne a disfunção vascular induzida pela hiperatividade β-adrenérgica

Abstract

The increase in sympathetic activity is involved with the genesis and maintenance of disease states that affect the cardiovascular system. Β-adrenergic hyperactivity induces the formation of local inflammatory factors in vascular tissue, leading to vascular dysfunction. A possible pharmacological strategy of controlling vascular injury by the inflammatory process is to inhibit the enzyme dipeptidyl peptidase-4. DPP-4 inhibitors are of the class of drugs used to treat type 2 diabetes mellitus by increasing the half-life of GLP- 1 and improve glycemic control. We aimed to test the hypothesis that the DPP-4 inhibitor reverses vascular dysfunction and attenuates the inflammatory process caused by β-adrenergic hyperactivity. Male Wistar rats (Rattus norvegicus) weighing between 300 and 350g were used. The animals were randomly divided into three groups: vehicle group (VHC), isoproterenol (non-selective βadrenergic agonist) (ISO) and isoproterenol group plus sitagliptin (DPP-4 inhibitor) (ISO + SITA). A human umbilical vein endothelial cell line (EAhy.926) and primary vascular smooth muscle cells (VSMC), obtained by the explant method of the thoracic aorta of wistar rats, were used. We have shown in our results that isoproterenol caused cardiac hypertrophy of 28% and sitagliptin was not able to prevent this response. There was no change in cardiorespiratory function. Inhibition of DPP-4 was able to prevent the increase in the contractile response to phenylephrine, in addition, it prevented the endothelial dysfunction caused by isoproterenol in vascular reactivity, observed by the mechanical removal of the endothelium. Chronic treatment with isoproterenol did not alter DPP-4 activity, but increased mRNA expression of the proinflammatory cytokines IL-1β (86%), IL-6 (45%) and MCP-1 (84%) in the aorta , while sitagliptin reduced to baseline. In vitro, isoproterenol did not alter the activity of DPP-4 and the expression of inflammatory cytokines in VSCV, but increased the activity of DPP-4 and inflammatory cytokines in endothelial cells (IL-1β, 49%, IL-6, 39%; MCP-1, 43%) and sitagliptin reduced to baseline. In conclusion, our study demonstrated that inhibition of DPP-4 by sitagliptin improves vascular dysfunction and significantly attenuates endothelial inflammation in an experimental model of β-adrenergic hyperactivity.