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

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.

CD8+T Cell-Related Gene Biomarkers in Macular Edema of Diabetic Retinopathy

“…Studies have illustrated that increased concentrations of various inflammatory mediators and pro-inflammatory cytokines in diabetic eyes are able to activate various related signaling pathways, leading to microvascular occlusion and destruction of the blood-retinal barrier, followed by vascular leakage, lack of capillary perfusion, neurodegeneration, and angiogenesis, which are consistent with the cytokine-mediated signaling pathways in our analysis (42). The activation, movement, migration and adhesion of cells provide the basis for the growth of neovascularization and the formation of FVM framework in DR (43). The adhesion of leukocytes in vascular endothelial cells is a favorable environmental factor for the development of inflammation, and KEGG also demonstrates that leukocytes are involved in transendothelial migration, which are important pathways in the formation and diffusion mechanism of DR inflammation (44,45).…”

Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications

“…Linagliptin reduced ET-1-induced basilar arteries contraction in diabetic rats, improving diabetic cerebrovascular dysfunction (175). In addition, evogliptin directly interferes with pathological retinal neovascularization (NV) by blocking VEGF-induced adenosine 5′-diphosphate ribosylation factor 6 (Arf6) activation in ECs (176).…”

Derivative Spectrophotometric Method Development and Validation for the Estimation of Evogliptin Tartrate in Pharmaceutical Dosage Form

“…In clinical research, 5 mg of evogliptin was once daily administrated in diabetic patients for 12 weeks and showed significant glucose lowing effects. [6][7][8] The literature survey indicates that few analytical methods involving liquid chromatography with tandem MS method was reported for determination of evogliptin tartrate in human plasma. 9 This technique is highly sensitive and for handling it qualified operator is needed.…”