AB038. Pathological neovascularization in retinopathy of prematurity is regulated by heme-derived iron trafficking

作     者：Tapan Agnihotri Nicholas Kim Gael Cagnone Jin Sung Kim Emilie Heckel Sheetal Pundir Perrine Gaub Florian Wunnemann Walter Szarek Hyman Schipper Jean-Sebastien Joyal 

作者机构：Department of Pharmacology and TherapeuticsMcGill UniversityMontréalQCCanada Department of PediatricsPharmacology and OphthalmologyCHU Sainte-Justine Research CenterUniversitéde MontrealMontréalQCCanada Department of ChemistryQueen’s UniversityKingstonONCanada 

出 版 物：《Annals of Eye Science》 (眼科学年鉴（英文）)

年 卷 期：2019年第1期

页      面：213-213页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：Retinopathy of prematurity(ROP) iron metabolism microglia 

摘      要：Background:Retinopathy of prematurity(ROP)is an eye disease of the immature newborn characterized by pathological neovascularization(NV).ROP classically arises due to changes in oxygen availability in the ***,other factors,such as red blood cell(RBC)transfusion,independently contribute to disease *** molecules,rich in RBC,are the primary source of endogenous *** is metabolized by heme oxygenase(HO)into biliverdin,carbon monoxide,and ferrous *** iron levels stabilize hypoxia-inducible factor 1α(HIF1α),the main transcription factor of vascular endothelial growth factor(VEGF)that drives *** we investigate the role of heme metabolism in pathological ***:ROP was studied using the well-characterized oxygen-induced retinopathy(OIR)mouse ***-type(WT)pups are exposed to high oxygen concentrations(FiO275%)for 5 days,from the post-natal day(P)7 to 12,and subsequently returned to room air until retinal collection at P12,P14,&*** are then analyzed via single-cell RNAseq,RT-qPCR,western blot,Prussian blue staining,and immunostaining techniques to elucidate the effect of OIR on iron metabolism and *** OIR,we quantified vaso-obliteration(VO)and pathologic neovascular(NV)areas at P17 to assess the effects of1 Hmox1 competitive inhibition,and2Hmox1 allosteric ***:Iron trafficking genes across different retinal cell-types were upregulated in OIR,including CP,FTH1,IREB2,TF,and ***,Prussian blue staining suggests iron accumulation in retinal vessels exposed to ***1 mRNA(n=7,P0.01 at P17)and protein expression(n=3,P0.05)were increased 3.8-fold from P12 to *** and single-cell RNAseq confirmed that Hmox1 predominantly resides in retinal microglial *** and allosterically Hmox1 inhibition decreased NV by 15%(n=15,P=0.02)and 60%(n=5,P0.01)***:Iron metabolism has seldom been explored in the context of *** microglial heme metabolis