PMID- 30133427
OWN - NLM
STAT- MEDLINE
DCOM- 20181211
LR  - 20240330
IS  - 1643-3750 (Electronic)
IS  - 1234-1010 (Print)
IS  - 1234-1010 (Linking)
VI  - 24
DP  - 2018 Aug 22
TI  - ATN-161 as an Integrin alpha5beta1 Antagonist Depresses Ocular Neovascularization by 
      Promoting New Vascular Endothelial Cell Apoptosis.
PG  - 5860-5873
LID - 10.12659/MSM.907446 [doi]
AB  - BACKGROUND ATN-161 (Ac-PHSCN-NH2), an antagonist of integrin alpha5beta1, 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-kappaB (NF-kappaB), 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 alpha5beta1 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-kappaB (NF-kappaB) 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-kappaB activation by ammonium 
      pyrrolidinedithiocarbamate (PDTC) reduced RNV and promoted cell apoptosis in 
      ocular NV. CONCLUSIONS Blocking integrin alpha5beta1 by ATN-161 reduced ocular NV by 
      inhibiting MMP-2/MMP-9 expression and promoting the cell apoptosis of ocular NV.
FAU - Sui, Ailing
AU  - Sui A
AD  - Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China (mainland).
FAU - Zhong, Yisheng
AU  - Zhong Y
AD  - Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China (mainland).
FAU - Demetriades, Anna M
AU  - Demetriades AM
AD  - Department of Ophthalmology, New York Presbyterian Hospital-Weill Cornell 
      Medicine, New York, NY, USA.
FAU - Shen, Jikui
AU  - Shen J
AD  - Departments of Ophthalmology and Neuroscience, The Johns Hopkins University 
      School of Medicine, Baltimore, MD, USA.
FAU - Su, Ting
AU  - Su T
AD  - Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China (mainland).
FAU - Yao, Yiyun
AU  - Yao Y
AD  - Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China (mainland).
FAU - Gao, Yushuo
AU  - Gao Y
AD  - Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China (mainland).
FAU - Zhu, Yanji
AU  - Zhu Y
AD  - Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China (mainland).
FAU - Shen, Xi
AU  - Shen X
AD  - Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China (mainland).
FAU - Xie, Bing
AU  - Xie B
AD  - Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China (mainland).
LA  - eng
PT  - Journal Article
DEP - 20180822
PL  - United States
TA  - Med Sci Monit
JT  - Medical science monitor : international medical journal of experimental and 
      clinical research
JID - 9609063
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Integrin alpha5beta1)
RN  - 0 (NF-kappa B)
RN  - 0 (Oligopeptides)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - XW0H5LE42K (acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide)
SB  - IM
MH  - Angiogenesis Inhibitors/pharmacology
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Choroidal Neovascularization/*drug therapy/metabolism
MH  - Disease Models, Animal
MH  - Endothelial Cells/metabolism
MH  - Eye/pathology
MH  - Female
MH  - Integrin alpha5beta1/*antagonists & inhibitors
MH  - Intravitreal Injections
MH  - Matrix Metalloproteinase 2/metabolism
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-kappa B/metabolism
MH  - Oligopeptides/*pharmacology
MH  - Retinal Neovascularization/*drug therapy/metabolism
PMC - PMC6116638
COIS- Conflict of interest None.
EDAT- 2018/08/23 06:00
MHDA- 2018/12/12 06:00
PMCR- 2018/08/22
CRDT- 2018/08/23 06:00
PHST- 2018/08/23 06:00 [entrez]
PHST- 2018/08/23 06:00 [pubmed]
PHST- 2018/12/12 06:00 [medline]
PHST- 2018/08/22 00:00 [pmc-release]
AID - 907446 [pii]
AID - 10.12659/MSM.907446 [doi]
PST - epublish
SO  - Med Sci Monit. 2018 Aug 22;24:5860-5873. doi: 10.12659/MSM.907446.