NRF2 regulates endothelial glycolysis and proliferation with miR-93 and mediates the effects of oxidized phospholipids on endothelial activation.
NRF2 regulates endothelial glycolysis and proliferation with miR-93 and mediates the effects of oxidized phospholipids on endothelial activation.
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DOI：
10.1093/nar/gkx1155
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发表时间：
2018-02-16
影响因子：
14.9
通讯作者：
Levonen AL
中科院分区：
文献类型：
--
作者：
Kuosmanen SM;Kansanen E;Kaikkonen MU;Sihvola V;Pulkkinen K;Jyrkkänen HK;Tuoresmäki P;Hartikainen J;Hippeläinen M;Kokki H;Tavi P;Heikkinen S;Levonen AL
磷脂，如1-棕榈酰-2-花生四烯酸酰-sn-甘油-3-磷酸胆碱（PAPC），是细胞膜的主要成分。它们暴露于活性氧产生氧化磷脂，通过内皮活化和功能障碍使其易于发展为慢性炎性疾病和代谢紊乱。虽然氧化型PAPC（oxPAPC）对内皮细胞的影响已被研究，引起生物反应的潜在分子机制仍然在很大程度上未知。在这里，我们研究了oxPAPC功能的分子机制，特别强调NRF 2调节的microRNAs（miRNA）在人脐静脉内皮细胞（HUVEC）利用miRNA分析，全球运行测序（GR 0-seq），全基因组NRF 2结合模型，和RNA测序（RNA-seq）与miRNA过表达和沉默。我们报道了内皮细胞活性的中心调节因子，KLF 2用于静止，PFKFB 3用于糖酵解，VEGFA，FOXO 1和MYC用于生长和增殖，在HUVEC中受到转录因子NRF 2和NRF 2调节的miR-106 b β 25簇成员miR-93的调节。从机制上讲，oxPAPC被发现诱导糖酵解和增殖NRF 2依赖性，和oxPAPC依赖性诱导的miR-106 b p25簇是由NRF 2介导的。此外，在NRF 2、miR-93和健康内皮的基本调节物之间建立了几个调节环，共同暗示NRF 2与miR-93一起控制静止和增殖内皮状态之间的转换。
Phospholipids, such as 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC), are the major components of cell membranes. Their exposure to reactive oxygen species creates oxidized phospholipids, which predispose to the development of chronic inflammatory diseases and metabolic disorders through endothelial activation and dysfunction. Although the effects of oxidized PAPC (oxPAPC) on endothelial cells have been previously studied, the underlying molecular mechanisms evoking biological responses remain largely unknown. Here, we investigated the molecular mechanisms of oxPAPC function with a special emphasis on NRF2-regulated microRNAs (miRNAs) in human umbilical vein endothelial cells (HUVECs) utilizing miRNA profiling, global run-on sequencing (GRO-seq), genome-wide NRF2 binding model, and RNA sequencing (RNA-seq) with miRNA overexpression and silencing. We report that the central regulators of endothelial activity, KLF2 for quiescence, PFKFB3 for glycolysis, and VEGFA, FOXO1 and MYC for growth and proliferation, are regulated by transcription factor NRF2 and the NRF2-regulated miR-106b∼25 cluster member, miR-93, in HUVECs. Mechanistically, oxPAPC was found to induce glycolysis and proliferation NRF2-dependently, and oxPAPC-dependent induction of the miR-106b∼25 cluster was mediated by NRF2. Additionally, several regulatory loops were established between NRF2, miR-93 and the essential regulators of healthy endothelium, collectively implying that NRF2 controls the switch between the quiescent and the proliferative endothelial states together with miR-93.
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影响因子：
16.6
作者：
Dong, Peng;Maddali, Manoj V.;Srimani, Jaydeep K.;Thelot, Francois;Nevins, Joseph R.;Mathey-Prevot, Bernard;You, Lingchong
通讯作者：
You, Lingchong
影响因子：
13.6
作者：
Andreou I;Sun X;Stone PH;Edelman ER;Feinberg MW
通讯作者：
Feinberg MW
影响因子：
4.3
作者：
Fang, Ling;Du, William W.;Yang, Burton B.
通讯作者：
Yang, Burton B.
影响因子：
4.4
作者：
Jeong G;Lim YH;Kim YK
通讯作者：
Kim YK
影响因子：
64.5
作者：
De Bock, Katrien;Georgiadou, Maria;Carmeliet, Peter
通讯作者：
Carmeliet, Peter