YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2

作者全名："Wang, Xiaotang; Fan, Wei; Li, Na; Ma, Yan; Yao, Mudi; Wang, Guoqing; He, Siyuan; Li, Wanqian; Tan, Jun; Lu, Qi; Hou, Shengping"

作者地址："[Wang, Xiaotang; Fan, Wei; Wang, Guoqing; He, Siyuan; Li, Wanqian; Tan, Jun; Hou, Shengping] Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China; [Wang, Xiaotang; Fan, Wei; Wang, Guoqing; He, Siyuan; Li, Wanqian; Tan, Jun; Hou, Shengping] Chongqing Key Lab Ophthalmol, Chongqing, Peoples R China; [Wang, Xiaotang; Fan, Wei; Wang, Guoqing; He, Siyuan; Li, Wanqian; Tan, Jun; Hou, Shengping] Chongqing Eye Inst, Chongqing, Peoples R China; [Wang, Xiaotang; Fan, Wei; Wang, Guoqing; He, Siyuan; Li, Wanqian; Tan, Jun; Hou, Shengping] Natl Clin Res Ctr Ocular Dis, Chongqing Branch, Chongqing, Peoples R China; [Li, Na] Chongqing Med Univ, Sch Basic Med Sci, Chongqing 400016, Peoples R China; [Ma, Yan; Yao, Mudi] Nanjing Med Univ, Affiliated Eye Hosp, Nanjing, Peoples R China; [Lu, Qi] Chongqing Med Univ, Childrens Hosp, Chongqing, Peoples R China; [Hou, Shengping] Capital Med Univ, Beijing Tongren Hosp, Beijing Inst Ophthalmol, Beijing Tongren Eye Ctr,Beijing Ophthalmol & Visua, Beijing 100730, Peoples R China"

通信作者："Hou, SP (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China.; Hou, SP (通讯作者)，Chongqing Key Lab Ophthalmol, Chongqing, Peoples R China.; Hou, SP (通讯作者)，Chongqing Eye Inst, Chongqing, Peoples R China.; Hou, SP (通讯作者)，Natl Clin Res Ctr Ocular Dis, Chongqing Branch, Chongqing, Peoples R China.; Hou, SP (通讯作者)，Capital Med Univ, Beijing Tongren Hosp, Beijing Inst Ophthalmol, Beijing Tongren Eye Ctr,Beijing Ophthalmol & Visua, Beijing 100730, Peoples R China."

来源：GENOME BIOLOGY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000978090800002

JCR分区：Q1

影响因子：10.1

年份：2023

卷号：24

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Angiogenesis; Retinal microglia; Posttranslational modifications (PTMs); Lactylation; YY1

摘要："BackgroundOcular neovascularization is a leading cause of blindness. Retinal microglia have been implicated in hypoxia-induced angiogenesis and vasculopathy, but the underlying mechanisms are not entirely clear. Lactylation is a novel lactate-derived posttranslational modification that plays key roles in multiple cellular processes. Since hypoxia in ischemic retinopathy is a precipitating factor for retinal neovascularization, lactylation is very likely to be involved in this process. The present study aimed to explore the role of lactylation in retinal neovascularization and identify new therapeutic targets for retinal neovascular diseases.ResultsMicroglial depletion by the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 suppresses retinal neovascularization in oxygen-induced retinopathy. Hypoxia increased lactylation in microglia and accelerates FGF2 expression, promoting retinal neovascularization. We identify 77 sites of 67 proteins with increased lactylation in the context of increased lactate under hypoxia. Our results show that the nonhistone protein Yin Yang-1 (YY1), a transcription factor, is lactylated at lysine 183 (K183), which is regulated by p300. Hyperlactylated YY1 directly enhances FGF2 transcription and promotes angiogenesis. YY1 mutation at K183 eliminates these effects. Overexpression of p300 increases YY1 lactylation and enhances angiogenesis in vitro and administration of the p300 inhibitor A485 greatly suppresses vascularization in vivo and in vitro.ConclusionsOur results suggest that YY1 lactylation in microglia plays an important role in retinal neovascularization by upregulating FGF2 expression. Targeting the lactate/p300/YY1 lactylation/FGF2 axis may provide new therapeutic targets for proliferative retinopathies."

基金机构：　

基金资助正文：