JP1,a polypeptide specifically targeting integrinαVβ3,ameliorates choroidal neovascularization and diabetic retinopathy in mice  

作　　者：Zhan Xie Xin-jing Wu Rui-wen Cheng Jia-hua Cui Song-tao Yuan Jian-wei Zhou Qing-huai Liu 

机构地区：[1]Department of Ophthalmology,First Affiliated Hospital of Nanjing Medical University,Nanjing 210029,China [2]Department of Molecular Cell Biology&Toxicology,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing 211166,China

出　　处：《Acta Pharmacologica Sinica》2023年第4期897-912,共16页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.81970821,81973156,81770973,81870694).

摘　　要：Anti-vascular endothelial growth factor(VEGF)drugs have revolutionized the treatment of neovascular eye diseases,but responses are incomplete in some patients.Recent evidence shows that integrins are involved in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy.JP1,derived from an optimized seven-amino-acid fragment of JWA protein,is a polypeptide specifically targeting integrinαVβ3.In this study we evaluated the efficacy of JP1 on laser-induced choroidal neovascularization(CNV)and retinal vascular leakage.CNV mice received a single intravitreal(IVT)injection of JP1(10,20,40μg)or ranibizumab(RBZ,10μg).We showed that JP1 injection dose-dependently inhibited laser-induced CNV;the effect of RBZ was comparable to that of 20μg JP1;a combined IVT injection of JP1(20μg)and RBZ(5μg)exerted a synergistic effect on CNV.In the 3rd month after streptozotocin injection,diabetic mice receiving IVT injection of JP1(40μg)or RBZ(10μg)once a week for 4 weeks showed significantly suppressed retinal vascular leakage.In both in vivo and in vitro experiments,JP1 counteracted oxidative stress and inflammation via inhibiting ROS/NF-κB signaling in microglial cells,and angiogenesis via modulating MEK1/2-SP1-integrinαVβ3 and TRIM25-SP1-MMP2 axes in vascular endothelial cells.In addition,intraperitoneal injection of JP1(1,5 or 10 mg)once every other day for 3 times also dose-dependently inhibited CNV.After intraperitoneal injection of FITC-labeled JP1(FITC-JP1)or FITC in laser-induced CNV mice,the fluorescence intensity in the CNV lesion was markedly increased in FITC-JP1 group,compared with that in FITC group,confirming that JP1 could penetrate the blood-retinal barrier to target CNV lesion.We conclude that JP1 can be used to design novel CNV-targeting therapeutic agents that may replace current invasive intraocular injections.

关 键 词：choroidal neovascularization diabetic retinopathy JP1 oxidative stress inflammation ANGIOGENESIS 

分 类 号：R722.1[医药卫生—儿科]