Faulty homocysteine recycling in diabetic retinopathy
作者机构：Department of OphthalmologyVisual Sciences and Anatomical SciencesWayne State University4717 St.AntoineDetroitMI 48201USA
出 版 物：《Eye and Vision》 (眼视光学杂志（英文）)
年 卷 期：2020年第7卷第1期
页 面：36-46页
核心收录：
学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 100212[医学-眼科学] 10[医学]
基 金：This work presented here was supported in parts by grants from the National Institutes of Health(EY014370,EY017313,EY022230) Thomas Foundation to RAK,and an unrestricted grant to the Ophthalmology Department from Research to Prevent Blindness
主 题：Diabetic retinopathy DNA methylation Homocysteine Hydrogen sulfide Mitophagy Epigenetics Mitochondria Oxidative stress Retina
摘 要：Background:Although hyperglycemia is the main instigator in the development of diabetic retinopathy,elevated circulating levels of a non-protein amino acid,homocysteine,are also associated with an increased risk of *** is recycled back to methionine by methylenetetrahydrofolate reductase(MTHFR)and/or transsulfurated by cystathionineβ-synthase(CBS)to form *** and other transsulfuration enzyme cystathionine-γ-lyase(CSE),through desulfuration,generates H_(2)*** cycle also regulates DNA methylation,an epigenetic modification associated with the gene *** aim of this study was to investigate homocysteine and its metabolism in diabetic ***:Homocysteine and H_(2)S levels were analyzed in the retina,and CBS,CSE and MTHFR in the retinal microvasculature from human donors with established diabetic *** damage was evaluated in retinal microvessels by quantifying enzymes responsible for maintaining mitochondrial dynamics(fission-fusionmitophagy).DNA methylation status of CBS and MTHFR promoters was examined using methylated DNA immunoprecipitation *** direct effect of homocysteine on mitochondrial damage was confirmed in human retinal endothelial cells(HRECs)incubated with 100μM ***:Compared to age-matched nondiabetic control human donors,retina from donors with established diabetic retinopathy had~3-fold higher homocysteine levels and~50%lower H_(2)S *** enzymes important for both transsulfuration and remethylation of homocysteine including CBS,CSE and MTHFR,were 40–60%lower in the retinal microvasculature from diabetic retinopathy *** the mitochondrial fission protein,dynamin related protein 1,and mitophagy markers optineurin and microtubule-associated protein 1A/1B-light chain 3(LC3),were upregulated,the fusion protein mitofusin 2 was *** the same retinal microvessel preparations from donors with diabetic retinopathy,DNA at the prom
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