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ATN-161 as an Integrin α5β1 Antagonist Depresses Ocular Neovascularization by Promoting New Vascular Endothelial Cell Apoptosis

BACKGROUND: ATN-161 (Ac-PHSCN-NH2), an antagonist of integrin α5β1, has shown an important influence in inhibiting tumor angiogenesis and metastasis of other tumor types. However, the mechanism of action of ATN-161 and whether it can inhibit ocular neovascularization (NV) are unclear. This study inv...

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Autores principales: Sui, Ailing, Zhong, Yisheng, Demetriades, Anna M., Shen, Jikui, Su, Ting, Yao, Yiyun, Gao, Yushuo, Zhu, Yanji, Shen, Xi, Xie, Bing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Scientific Literature, Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116638/
https://www.ncbi.nlm.nih.gov/pubmed/30133427
http://dx.doi.org/10.12659/MSM.907446
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author Sui, Ailing
Zhong, Yisheng
Demetriades, Anna M.
Shen, Jikui
Su, Ting
Yao, Yiyun
Gao, Yushuo
Zhu, Yanji
Shen, Xi
Xie, Bing
author_facet Sui, Ailing
Zhong, Yisheng
Demetriades, Anna M.
Shen, Jikui
Su, Ting
Yao, Yiyun
Gao, Yushuo
Zhu, Yanji
Shen, Xi
Xie, Bing
author_sort Sui, Ailing
collection PubMed
description BACKGROUND: ATN-161 (Ac-PHSCN-NH2), an antagonist of integrin α5β1, has shown an important influence in inhibiting tumor angiogenesis and metastasis of other tumor types. However, the mechanism of action of ATN-161 and whether it can inhibit ocular neovascularization (NV) are unclear. This study investigated the role of ATN-161 in regulating ocular angiogenesis in mouse models and explored the underlying signaling pathway. MATERIAL/METHODS: An oxygen-induced retinopathy (OIR) mouse model and a laser-induced choroidal neovascularization (CNV) mouse model were used to test integrin α5β1 expression and the effect of ATN-161 on ocular NV by immunofluorescence staining, Western blot analysis, and flat-mount analysis. The activation of nuclear factor-κB (NF-κB), matrix metalloproteinase-2/9 (MMP-2/9), and cell apoptosis were detected by immunofluorescence staining, Western blot, real-time RT-PCR, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). The cell proliferation was detected by BrdU labeling. RESULTS: In OIR and CNV mice, the protein expression level of integrin α5β1 increased compared with that in age-matched controls. The mice given ATN-161 had significantly reduced retinal neovascularization (RNV) and CNV. Blocking integrin α5β1 by ATN-161 strongly inhibited nuclear factor-κB (NF-κB) activation and matrix metalloproteinase-2/9 (MMP-2/9) expression and promoted cell apoptosis, but the effect of ATN-161 on proliferation in CNV mice was indirect and required the inhibition of neovascularization. Inhibiting NF-κB activation by ammonium pyrrolidinedithiocarbamate (PDTC) reduced RNV and promoted cell apoptosis in ocular NV. CONCLUSIONS: Blocking integrin α5β1 by ATN-161 reduced ocular NV by inhibiting MMP-2/MMP-9 expression and promoting the cell apoptosis of ocular NV.
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spelling pubmed-61166382018-08-31 ATN-161 as an Integrin α5β1 Antagonist Depresses Ocular Neovascularization by Promoting New Vascular Endothelial Cell Apoptosis Sui, Ailing Zhong, Yisheng Demetriades, Anna M. Shen, Jikui Su, Ting Yao, Yiyun Gao, Yushuo Zhu, Yanji Shen, Xi Xie, Bing Med Sci Monit Lab/In Vitro Research BACKGROUND: ATN-161 (Ac-PHSCN-NH2), an antagonist of integrin α5β1, has shown an important influence in inhibiting tumor angiogenesis and metastasis of other tumor types. However, the mechanism of action of ATN-161 and whether it can inhibit ocular neovascularization (NV) are unclear. This study investigated the role of ATN-161 in regulating ocular angiogenesis in mouse models and explored the underlying signaling pathway. MATERIAL/METHODS: An oxygen-induced retinopathy (OIR) mouse model and a laser-induced choroidal neovascularization (CNV) mouse model were used to test integrin α5β1 expression and the effect of ATN-161 on ocular NV by immunofluorescence staining, Western blot analysis, and flat-mount analysis. The activation of nuclear factor-κB (NF-κB), matrix metalloproteinase-2/9 (MMP-2/9), and cell apoptosis were detected by immunofluorescence staining, Western blot, real-time RT-PCR, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). The cell proliferation was detected by BrdU labeling. RESULTS: In OIR and CNV mice, the protein expression level of integrin α5β1 increased compared with that in age-matched controls. The mice given ATN-161 had significantly reduced retinal neovascularization (RNV) and CNV. Blocking integrin α5β1 by ATN-161 strongly inhibited nuclear factor-κB (NF-κB) activation and matrix metalloproteinase-2/9 (MMP-2/9) expression and promoted cell apoptosis, but the effect of ATN-161 on proliferation in CNV mice was indirect and required the inhibition of neovascularization. Inhibiting NF-κB activation by ammonium pyrrolidinedithiocarbamate (PDTC) reduced RNV and promoted cell apoptosis in ocular NV. CONCLUSIONS: Blocking integrin α5β1 by ATN-161 reduced ocular NV by inhibiting MMP-2/MMP-9 expression and promoting the cell apoptosis of ocular NV. International Scientific Literature, Inc. 2018-08-22 /pmc/articles/PMC6116638/ /pubmed/30133427 http://dx.doi.org/10.12659/MSM.907446 Text en © Med Sci Monit, 2018 This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) )
spellingShingle Lab/In Vitro Research
Sui, Ailing
Zhong, Yisheng
Demetriades, Anna M.
Shen, Jikui
Su, Ting
Yao, Yiyun
Gao, Yushuo
Zhu, Yanji
Shen, Xi
Xie, Bing
ATN-161 as an Integrin α5β1 Antagonist Depresses Ocular Neovascularization by Promoting New Vascular Endothelial Cell Apoptosis
title ATN-161 as an Integrin α5β1 Antagonist Depresses Ocular Neovascularization by Promoting New Vascular Endothelial Cell Apoptosis
title_full ATN-161 as an Integrin α5β1 Antagonist Depresses Ocular Neovascularization by Promoting New Vascular Endothelial Cell Apoptosis
title_fullStr ATN-161 as an Integrin α5β1 Antagonist Depresses Ocular Neovascularization by Promoting New Vascular Endothelial Cell Apoptosis
title_full_unstemmed ATN-161 as an Integrin α5β1 Antagonist Depresses Ocular Neovascularization by Promoting New Vascular Endothelial Cell Apoptosis
title_short ATN-161 as an Integrin α5β1 Antagonist Depresses Ocular Neovascularization by Promoting New Vascular Endothelial Cell Apoptosis
title_sort atn-161 as an integrin α5β1 antagonist depresses ocular neovascularization by promoting new vascular endothelial cell apoptosis
topic Lab/In Vitro Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116638/
https://www.ncbi.nlm.nih.gov/pubmed/30133427
http://dx.doi.org/10.12659/MSM.907446
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