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

Retinal disease: How anti-diabetic drug can help eyes Pathological retinal angiogenesis, the damaging formation of new blood vessels in the retina, which is associated with various diseases including diabetes, could be reduced using the anti-diabetic drug evogliptin to inhibit the effects of a vascular growth factor. Researchers in South Korea led by Wonhee Suh and Koung Li Kim at Chung-Ang University in Seoul investigated the molecular mechanism underlying evogliptin's effects. In studies using mice and cultured human cells they found that evogliptin inhibited the activation of signaling molecules that mediate the effects of vascular endothelial growth factor. They also identified an enzyme in the signaling pathway that is directly inhibited by evogliptin. The results offer molecular level insights into the additional benefit gained from using evogliptin to treat diabetes, distinct from the drug's established effects in lowering blood glucose. 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.