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

Experimental & Molecular Medicine 2020년 52권 10호 p.5 ~ 5
서송이, 김미경, 김율이, 여영주, 김경리, 서원희,
소속 상세정보
서송이 ( Seo Song-Yi ) - Chung-Ang University College of Pharmacy Department of Global Innovative Drug
김미경 ( Kim Mi-Kyung ) - Dong-A ST Co. Ltd. Drug Discovery Research Laboratories
김율이 ( Kim Ryul-I ) - Chung-Ang University College of Pharmacy Department of Global Innovative Drug
여영주 ( Yeo Yeong-Ju ) - Chung-Ang University College of Pharmacy Department of Global Innovative Drug
김경리 ( Kim Koung-Li ) - Chung-Ang University College of Pharmacy Department of Global Innovative Drug
서원희 ( Suh Won-Hee ) - Chung-Ang University College of Pharmacy Department of Global Innovative Drug

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.

키워드

Growth factor signalling; Vascular diseases

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