Evogliptin, a dipeptidyl peptidase-4 inhibitor, attenuates pathological retinal angiogenesis by suppressing vascular endothelial growth factor-induced Arf6 activation

Songyi Seo,Ryul-I Kim,Yeongju Yeo,Mi-Kyung Kim,Koung Li Kim,Wonhee Suh

doi:10.1038/s12276-020-00512-8

Abstract

Dipeptidyl peptidase-4 (DPP-4) inhibitors are used for the treatment of type 2 diabetes mellitus (DM). Recent studies have shown that beyond their effect in lowing glucose, DPP-4 inhibitors mitigate DM-related microvascular complications, such as diabetic retinopathy. However, the mechanism by which pathological retinal neovascularization, a major clinical manifestation of diabetic retinopathy, is inhibited is unclear. This study sought to examine the effects of evogliptin, a potent DPP-4 inhibitor, on pathological retinal neovascularization in mice and elucidate the mechanism by which evogliptin inhibits angiogenesis mediated by vascular endothelial growth factor (VEGF), a key factor in the vascular pathogenesis of proliferative diabetic retinopathy (PDR). In a murine model of PDR, an intravitreal injection of evogliptin significantly suppressed aberrant retinal neovascularization. In human endothelial cells, evogliptin reduced VEGF-induced angiogenesis. Western blot analysis showed that evogliptin inhibited the phosphorylation of signaling molecules associated with VEGF-induced cell adhesion and migration. Moreover, evogliptin substantially inhibited the VEGF-induced activation of adenosine 5′-diphosphate ribosylation factor 6 (Arf6), a small guanosine 5′-triphosphatase (GTPase) that regulates VEGF receptor 2 signal transduction. Direct activation of Arf6 using a chemical inhibitor of Arf-directed GTPase-activating protein completely abrogated the inhibitory effect of evogliptin on VEGF-induced activation of the angiogenic signaling pathway, which suggests that evogliptin suppresses VEGF-induced angiogenesis by blocking Arf6 activation. Our results provide insights into the molecular mechanism of the direct inhibitory effect of the DPP-4 inhibitor evogliptin on pathological retinal neovascularization. In addition to its glucose-lowering effect, the antiangiogenic effect of evogliptin could also render it beneficial for individuals with PDR.

Highlights

Dipeptidyl peptidase-4 (DPP-4) is a widely expressed enzyme that selectively cleaves peptides with a proline or alanine at the second position after the amino-terminus
As the present study aimed to investigate the direct local effect of evogliptin, a DPP-4 inhibitor, on pathological NV in the eye, evogliptin was intravitreally injected into mice with Oxygen-induced retinopathy (OIR) that displayed the hallmark features of aberrant retinal NV in proliferative diabetic retinopathy (DR) (PDR)
In the present study, we have demonstrated that an intravitreal injection of the DPP-4 inhibitor evogliptin ameliorated pathological retinal NV in a murine model representing the vascular pathological features of PDR and reduced vascular endothelial growth factor (VEGF)-mediated angiogenesis in human primary endothelial cells

Summary

Introduction

Dipeptidyl peptidase-4 (DPP-4) is a widely expressed enzyme that selectively cleaves peptides with a proline or alanine at the second position after the amino-terminus. A cross-sectional study of patients with type 1 DM showed that serum DPP-4 activity in patients with DR was significantly higher than that in patients without DR, which demonstrates the possible association of DPP-4 activity and DR5 Another clinical trial study reported that treatment with saxagliptin normalized retinal capillary flow and improved retinal vascular function in patients with type 2 DM6. These clinical data imply that DPP-4 inhibitors may exert direct beneficial effects against DR independent of their improvement of glycemic control, not much experimental evidence indicating the mechanism by which DPP-4 inhibitors prevent retinal vascular pathogenesis in PDR is available

Methods

Results

Conclusion