TY - JOUR
T1 - ATN-161 as an integrin α5β1 antagonist depresses ocular neovascularization by promoting new vascular endothelial cell apoptosis
AU - Sui, Ailing
AU - Zhong, Yisheng
AU - Demetriades, Anna M.
AU - Shen, Jikui
AU - Su, Ting
AU - Yao, Yiyun
AU - Gao, Yushuo
AU - Zhu, Yanji
AU - Shen, Xi
AU - Xie, Bing
N1 - Funding Information:
Supported by the National Natural Science Foundation of China 81470639 and 81570853; Shanghai Natural Science Foundation Grant 14411968400; and 2015 Doctoral Innovation Fund Projects BXJ201414 from Shanghai Jiao Tong University School of Medicine, China
Funding Information:
Bing Xie, e-mail: brinkleybing@126.com, Xi Shen: e-mail: carl_shen2005@126.com Supported by the National Natural Science Foundation of China 81470639 and 81570853; Shanghai Natural Science Foundation Grant 14411968400; and 2015 Doctoral Innovation Fund Projects BXJ201414 from Shanghai Jiao Tong University School of Medicine, China
Publisher Copyright:
© Med Sci Monit.
PY - 2018/8/22
Y1 - 2018/8/22
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Integrin alpha5beta1
KW - Matrix metalloproteinases
KW - NF-kappa B
KW - Neovascularization, Pathologic
UR - http://www.scopus.com/inward/record.url?scp=85053696324&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053696324&partnerID=8YFLogxK
U2 - 10.12659/MSM.907446
DO - 10.12659/MSM.907446
M3 - Article
C2 - 30133427
AN - SCOPUS:85053696324
SN - 1234-1010
VL - 24
SP - 5860
EP - 5873
JO - Medical Science Monitor
JF - Medical Science Monitor
ER -