m6A-甲基化酶 METTL3 通过调节 RPE 细胞的代谢重编程促进视网膜血管生成。

IF 9.3 1区 医学 Q1 IMMUNOLOGY
Qian Zhou, Xianyang Liu, Huiping Lu, Na Li, Jiayu Meng, Jiaxing Huang, Zhi Zhang, Jiangyi Liu, Wei Fan, Wanqian Li, Xingran Li, Xiaoyan Liu, Hangjia Zuo, Peizeng Yang, Shengping Hou
{"title":"m6A-甲基化酶 METTL3 通过调节 RPE 细胞的代谢重编程促进视网膜血管生成。","authors":"Qian Zhou, Xianyang Liu, Huiping Lu, Na Li, Jiayu Meng, Jiaxing Huang, Zhi Zhang, Jiangyi Liu, Wei Fan, Wanqian Li, Xingran Li, Xiaoyan Liu, Hangjia Zuo, Peizeng Yang, Shengping Hou","doi":"10.1186/s12974-024-03279-1","DOIUrl":null,"url":null,"abstract":"<p><p>Retinal neovascularization (RNV) disease is one of the leading causes of blindness, yet the molecular underpinnings of this condition are not well understood. To delve into the critical aspects of cell-mediated angiogenesis, we analyzed our previously published single-cell data. Our analysis revealed that retinal pigment epithelium (RPE) cells serve a crucial promotional function in angiogenesis. RPE cells were regulated by N6-methyladenosine (m6A). Next, we detected several critical m6A methylase in hypoxic ARPE-19 cells and in oxygen-induced retinopathy (OIR) mice, our results revealed a significant decrease in the level of methyltransferase like 3 (METTL3). METTL3 specific inhibitor STM2457 intravitreal injection or METTL3 conditional knockout mice both showed a significantly reduced neovascularization area of retina. Additionally, the angiogenesis-related abilities of human retinal endothelial cells (HRECs) were diminished after co-cultured with ARPE-19 treated with STM2457 or sh-METTL3 in vitro. Furthermore, through the integration of Methylated RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing, we discovered that the metabolic enzyme quinolinate phosphoribosyltransferase (QPRT) was directly modified by METTL3 and recognized by the YTH N6-methyladenosine RNA binding protein C1 (YTHDC1). Moreover, after over-expressing QPRT, the angiogenic abilities of HRECs were improved through the phosphorylated phosphatidylinositol-3-kinase (p-PI3K)/ phosphorylated threonine kinase (p-AKT) pathway. Collectively, our study provided a novel therapeutic target for retinal angiogenesis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"289"},"PeriodicalIF":9.3000,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539582/pdf/","citationCount":"0","resultStr":"{\"title\":\"m6A-methylase METTL3 promotes retinal angiogenesis through modulation of metabolic reprogramming in RPE cells.\",\"authors\":\"Qian Zhou, Xianyang Liu, Huiping Lu, Na Li, Jiayu Meng, Jiaxing Huang, Zhi Zhang, Jiangyi Liu, Wei Fan, Wanqian Li, Xingran Li, Xiaoyan Liu, Hangjia Zuo, Peizeng Yang, Shengping Hou\",\"doi\":\"10.1186/s12974-024-03279-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Retinal neovascularization (RNV) disease is one of the leading causes of blindness, yet the molecular underpinnings of this condition are not well understood. To delve into the critical aspects of cell-mediated angiogenesis, we analyzed our previously published single-cell data. Our analysis revealed that retinal pigment epithelium (RPE) cells serve a crucial promotional function in angiogenesis. RPE cells were regulated by N6-methyladenosine (m6A). Next, we detected several critical m6A methylase in hypoxic ARPE-19 cells and in oxygen-induced retinopathy (OIR) mice, our results revealed a significant decrease in the level of methyltransferase like 3 (METTL3). METTL3 specific inhibitor STM2457 intravitreal injection or METTL3 conditional knockout mice both showed a significantly reduced neovascularization area of retina. Additionally, the angiogenesis-related abilities of human retinal endothelial cells (HRECs) were diminished after co-cultured with ARPE-19 treated with STM2457 or sh-METTL3 in vitro. Furthermore, through the integration of Methylated RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing, we discovered that the metabolic enzyme quinolinate phosphoribosyltransferase (QPRT) was directly modified by METTL3 and recognized by the YTH N6-methyladenosine RNA binding protein C1 (YTHDC1). Moreover, after over-expressing QPRT, the angiogenic abilities of HRECs were improved through the phosphorylated phosphatidylinositol-3-kinase (p-PI3K)/ phosphorylated threonine kinase (p-AKT) pathway. Collectively, our study provided a novel therapeutic target for retinal angiogenesis.</p>\",\"PeriodicalId\":16577,\"journal\":{\"name\":\"Journal of Neuroinflammation\",\"volume\":\"21 1\",\"pages\":\"289\"},\"PeriodicalIF\":9.3000,\"publicationDate\":\"2024-11-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539582/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Neuroinflammation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12974-024-03279-1\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Neuroinflammation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12974-024-03279-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

视网膜新生血管(RNV)疾病是导致失明的主要原因之一,但人们对这种疾病的分子基础却不甚了解。为了深入研究细胞介导的血管生成的关键环节,我们分析了之前发表的单细胞数据。我们的分析表明,视网膜色素上皮细胞(RPE)在血管生成中起着至关重要的促进作用。RPE 细胞受 N6-甲基腺苷(m6A)的调控。接下来,我们在缺氧的 ARPE-19 细胞和氧诱导视网膜病变(OIR)小鼠中检测了几种关键的 m6A 甲基化酶,结果发现类似甲基转移酶 3(METTL3)的水平显著下降。METTL3特异性抑制剂STM2457静脉注射或METTL3条件性基因敲除小鼠均显示视网膜新生血管面积明显减少。此外,在体外与经 STM2457 或 sh-METTL3 处理的 ARPE-19 共同培养后,人视网膜内皮细胞(HRECs)的血管生成相关能力减弱。此外,通过整合甲基化 RNA 免疫共沉淀(MeRIP)测序和 RNA 测序,我们发现代谢酶喹啉酸磷酸核糖转移酶(QPRT)被 METTL3 直接修饰,并被 YTH N6-甲基腺苷 RNA 结合蛋白 C1(YTHDC1)识别。此外,过度表达QPRT后,HRECs的血管生成能力通过磷酸化磷脂酰肌醇-3-激酶(p-PI3K)/磷酸化苏氨酸激酶(p-AKT)途径得到改善。总之,我们的研究为视网膜血管生成提供了一个新的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
m6A-methylase METTL3 promotes retinal angiogenesis through modulation of metabolic reprogramming in RPE cells.

Retinal neovascularization (RNV) disease is one of the leading causes of blindness, yet the molecular underpinnings of this condition are not well understood. To delve into the critical aspects of cell-mediated angiogenesis, we analyzed our previously published single-cell data. Our analysis revealed that retinal pigment epithelium (RPE) cells serve a crucial promotional function in angiogenesis. RPE cells were regulated by N6-methyladenosine (m6A). Next, we detected several critical m6A methylase in hypoxic ARPE-19 cells and in oxygen-induced retinopathy (OIR) mice, our results revealed a significant decrease in the level of methyltransferase like 3 (METTL3). METTL3 specific inhibitor STM2457 intravitreal injection or METTL3 conditional knockout mice both showed a significantly reduced neovascularization area of retina. Additionally, the angiogenesis-related abilities of human retinal endothelial cells (HRECs) were diminished after co-cultured with ARPE-19 treated with STM2457 or sh-METTL3 in vitro. Furthermore, through the integration of Methylated RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing, we discovered that the metabolic enzyme quinolinate phosphoribosyltransferase (QPRT) was directly modified by METTL3 and recognized by the YTH N6-methyladenosine RNA binding protein C1 (YTHDC1). Moreover, after over-expressing QPRT, the angiogenic abilities of HRECs were improved through the phosphorylated phosphatidylinositol-3-kinase (p-PI3K)/ phosphorylated threonine kinase (p-AKT) pathway. Collectively, our study provided a novel therapeutic target for retinal angiogenesis.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Journal of Neuroinflammation
Journal of Neuroinflammation 医学-神经科学
CiteScore
15.90
自引率
3.20%
发文量
276
审稿时长
1 months
期刊介绍: The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信