Dipeptidyl peptidase‐4 inhibitor improves neovascularization by increasing circulating endothelial progenitor cells

Abstract

BACKGROUND AND PURPOSE Current methods used to treat critical limb ischaemia (CLI) are hampered by a lack of effective strategies, therefore, therapeutic vasculogenesis may open up a new field for the treatment of CLI. In this study we investigated the ability of the DPP‐4 inhibitor, sitagliptin, originally used as a hypoglycaemic agent, to induce vasculogenesis in vivo. EXPERIMENTAL APPROACH Sitagliptin were administered daily to C57CL/B6 mice and eGFP transgenic mouse bone marrow‐transplanted ICR mice that had undergone hindlimb ischaemic surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and circulating levels of endothelial progenitor cells (EPCs) respectively. Cell surface markers of EPCs and endothelial NOS (eNOS) in vessels were studied. KEY RESULTS Sitagliptin elevated plasma glucagon‐like peptide‐1 (GLP‐1) levels in mice subjected to ischaemia, decreased plasma dipeptidyl peptidase‐4 (DPP‐4) concentration, and augmented ischaemia‐induced increases in stromal cell‐derived factor‐1 (SDF‐1) in a dose‐dependent manner. Blood flow in the ischaemic limb was significantly improved in mice treated with sitagliptin. Circulating levels of EPCs were also increased after sitagliptin treatment. Sitagliptin also enhanced the expression of CD 34 and eNOS in ischaemic muscle. In addition, sitagliptin promoted EPC mobilization and homing to ischaemic tissue in eGFP transgenic mouse bone marrow‐transplanted ICR mice. CONCLUSION AND IMPLICATIONS Circulating EPC levels and neovasculogenesis were augmented by the DPP‐4 inhibitor, sitagliptin and this effect was dependent on an eNOS‐related pathway in a mouse model of hindlimb ischaemia. The results indicate that oral administration of sitagliptin has therapeutic potential as an inducer of vasculogenesis.

Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors

“…Additionally, as compared to a lower dosage of sitagliptin, the higher dosage of sitagliptin was more effective in up-regulating the EPC expression in the renal parenchyma. In this way, our study is consistent with the results of recent studies [27,[29][30][31][32] . Our finding of enhanced EPC expression in acute IR kidney injury supports the essential role of EPCs in repairing injured endothelial cells and participation in angiogenesis in response to ischemic insult from acute IR injury.…”

“…Interestingly, another experimental study has revealed that sitagliptin therapy enhanced neovascularization through increasing circulating number of EPCs [29] . Additionally, a clinical observational study has also shown that sitagliptin therapy increases the circulating level of EPCs in patients with type II diabetes mellitus [29,30] .…”

“…Interestingly, another experimental study has revealed that sitagliptin therapy enhanced neovascularization through increasing circulating number of EPCs [29] . Additionally, a clinical observational study has also shown that sitagliptin therapy increases the circulating level of EPCs in patients with type II diabetes mellitus [29,30] . Furthermore, other recent studies have also shown that sitagliptin therapy prevented the propagation of carotid intima-media thickening [31] and protected against ischemia-related left ventricular dysfunction [32] .…”

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

“…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).…”

Endothelial Loss and Repair in the Vascular Complications of Diabetes

“…60 Similar findings have also been reported in experimental diabetic cardiomyopathy 44 and hindlimb ischemia. 61 The effects of DPP4 inhibition have also been examined in patients with T2DM in whom 4 weeks of treatment increased both plasma SDF-1 level and the circulating EPC (CD34 + / VEGFR2 + ) count. 62 However, whether these SDF-1-related mechanisms may also account for the diminution in cardiovascular events observed in meta-analyses of DPP-4 treatment in diabetic patients 63 remains speculative.…”