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22 August 2018 : Laboratory Research  

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

Ailing Sui1ABCDEFG, Yisheng Zhong1BCD, Anna M. Demetriades2CEF, Jikui Shen3CEF, Ting Su1EF, Yiyun Yao1BCD, Yushuo Gao1BE, Yanji Zhu1EF, Xi Shen1AFG, Bing Xie1AEFG*

DOI: 10.12659/MSM.907446

Med Sci Monit 2018; 24: LBR5860-5873

Abstract

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 AND METHODS: An oxygen-induced retinopathy (OIR) mouse model and a laser-induced choroidal neovascularization (CNV) mouse model were used to test integrin a5b1 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 a5b1 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.

Keywords: Integrin alpha5beta1, Matrix Metalloproteinases, Neovascularization, Pathologic

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750