Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways

Abstract

Evidence from both clinical and experimental studies indicates that Di-peptidyl peptidase-IV (DPP-4) inhibition may mediate favorable effects on the cardiovascular system. The objective of this study was to examine the acute effects of DPP-4 inhibition on vascular responses and to study the underlying mechanisms of alteration in tone. Aortic segments from C57BL/6 mice were treated with vasoconstrictors and exposed to various doses of alogliptin, a selective DPP-4 inhibitor. Vasodilator responses were evaluated using pathway specific antagonists to elucidate mechanisms of response. In parallel experiments, cultured human umbilical vein endothelial cells (HUVEC) were exposed to varying concentrations of alogliptin to evaluate the effects on candidate vasodilator pathways. Alogliptin relaxed phenylephrine and U46619 pre-constricted aortic segments in a dose dependent manner. Relaxation responses were not affected by the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin fragment 9–39 (88±6 vs. 91±2, p<0.001). Vascular relaxation to alogliptin was significantly decreased by endothelial denudation, L-NG-monomethyl-arginine citrate (L-NMMA) and by the soluble guanylate cyclase inhibitor ODQ. DPP-4 inhibition induced relaxation was completely abolished by a combination of L-NMMA, charybdotoxin and apamin. Incubation of HUVECs with alogliptin resulted in eNOS and Akt phosphorylation (Ser1177 and Ser473 respectively) paralleled by a rapid increase in nitric oxide. Inhibition of Src kinase decreased eNOS and Akt phosphorylation, in contrast to a lack of any effect on insulin mediated activation of the eNOS-Akt, suggesting that alogliptin mediates vasodilation through Src kinase mediated effects on eNOS-Akt. DPP-4 inhibition by alogliptin mediates rapid vascular relaxation via GLP-1 independent, Src-Akt-eNOS mediated NO release and the activation of vascular potassium channels.

Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe −/− mice

“…In addition, we cannot exclude the fact that improved glucose tolerance in sitagliptin-treated mice may influence vascular chemokine or adhesion molecule levels or secondary effects on cell migration. Another limitation of this study is that the recently described beneficial cardiovascular effects of both GLP-1-mediated and direct effects of DPP-IV inhibition on endothelial nitric oxide synthase have not been investigated in our model [6,29].…”

Vildagliptin Stimulates Endothelial Cell Network Formation and Ischemia-induced Revascularization via an Endothelial Nitric-oxide Synthase-dependent Mechanism

“…Response to Vildagliptin-It has been reported that DPP-4 inhibition mediates rapid vascular relaxation through activation of Src-Akt-eNOS signaling that is independent of GLP-1 (12). To determine whether Src kinase is involved in vildagliptin-stimulated endothelial cell network formation, HUVECs were pretreated with a Src kinase inhibitor, PP2, followed by treatment with vildagliptin or GLP-1.…”

“…Treatment with sitagliptin attenuated intimal hyperplasia in response to vascular injury in rats (9), and both sitagliptin and alogliptin reduced atherosclerotic lesions in a mouse model (10,11). Alogliptin treatment was also found to modulate endotheliumdependent vasodilation in mouse aortic segments (12), and sita-gliptin augments neovascularization by increasing circulating endothelial progenitor cells in vivo (13). Treatment with sitagliptin in diabetic patients reverses vascular endothelial dysfunction as assessed by increased flow-mediated dilation and also increases circulating adiponectin levels (14).…”

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

“…Several studies in animal models support the evidence of DPP4 inhibition in improving endothelial function and blood pressure [158,159]. In isolated aorta rings incubated with DPP4-inhibitor, the relaxant effect of DPP4-inhibitor is GLP-1 independent and results from Akt posphorylation and eNOS activation with a rapid increase in NO levels [160]. Saxagliptin treatment has been shown to reduce blood pressure levels in the spontaneously hypertensive rats with a concomitant increase of aortic and glomerular NO release and comparable reductions in peroxynitrite levels [161].…”