title: Therapeutic efficacy of a novel non-peptide αvβ3 integrin antagonist for pathological retinal angiogenesis in mice.
abstract: αvβ3 integrin has been reported as a promising therapeutic target for angiogenesis. In the present study, we tested the antiangiogenic activity of 3-[3-(6-guanidino-1-oxoisoindolin-2-yl) propanamido]-3-(pyridin-3-yl) propanoic acid dihydrochloride (GOPPP), a novel non-peptide αvβ3 antagonist. Both human umbilical vein endothelial cells (HUVECs) and a mouse model of oxygen-induced retinopathy (OIR) were investigated separately. HUVEC adhesion, proliferation, migration, ERK1/2 and Akt phosphorylation were assessed. C57BL/6 mice were used for the studies in the OIR model. After exposure to 75% oxygen from postnatal day (PD) 7 to PD12, the mice were returned to room air, and GOPPP was intravitreally administered on PD12. Retinal neovascularization was evaluated on PD17. Hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels and ERK1/2 phosphorylation were determined by Western blot analysis of retina proteins. GOPPP significantly inhibited the pro-angiogenic effects of vitronectin on HUVECs, including adhesion, proliferation, and migration, and inhibited ERK1/2 and Akt phosphorylation. Retinal neovascularization in the OIR model was significantly suppressed by intravitreal administration of 50 ng GOPPP. The pro-angiogenic factors HIF-1α and VEGF induced by hypoxia were significantly inhibited by GOPPP in OIR mice. GOPPP administration also inhibited ERK1/2 phosphorylation in the OIR model. These results indicate that GOPPP, a novel αvβ3 integrin antagonist, may have potential for the treatment of pathological retinal angiogenesis.
authors.affiliation: Department of Pharmacology, Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, China.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Biopharmaceutics, West China School of Pharmacy, Sichuan University, Chengdu, China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, China.
authors.forename: Liang-Fen
authors.initials: LF
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Kuang
authors.affiliation: Department of Medical Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, China.
authors.forename: Zhi-Xiong
authors.initials: ZX
authors.lastname: Hang
authors.affiliation: Department of Medical Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, China. Electronic address: dengyong@scu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Pharmacology, Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, China. Electronic address: dujr_1@163.com.
authors.forename: Jun-Rong
authors.initials: JR
authors.lastname: Du
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D039302:Integrin alphaVbeta3
keywords: Angiogenesis; Integrin avβ3; Non-peptide integrin antagonist; Oxygen-induced retinopathy