Suppression of transient receptor potential canonical channel 4 inhibits vascular endothelial growth factor-induced retinal neovascularization

Cell Calcium ◽  
2015 ◽  
Vol 57 (2) ◽  
pp. 101-108 ◽  
Author(s):  
Hyun Beom Song ◽  
Hyoung-Oh Jun ◽  
Jin Hyoung Kim ◽  
Marcus Fruttiger ◽  
Jeong Hun Kim
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Retinal Neovascularization ◽  
Vascular Endothelial ◽  
Transient Receptor Potential Canonical ◽  
Transient Receptor ◽  
Endothelial Growth Factor

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

2020 ◽  
Vol 52 (10) ◽  
pp. 1744-1753
Author(s):  
Songyi Seo ◽  
Mi-Kyung Kim ◽  
Ryul-I Kim ◽  
Yeongju Yeo ◽  
Koung Li Kim ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Diabetic Retinopathy ◽  
Growth Factor ◽  
Dipeptidyl Peptidase ◽  
Inhibitory Effect ◽  
Retinal Neovascularization ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Dipeptidyl Peptidase 4 ◽  
Endothelial Growth Factor

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.

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