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.

中文翻译：

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NRF2 通过 miR-93 调节内皮糖酵解和增殖，并介导氧化磷脂对内皮活化的影响

磷脂，例如1-棕榈酰-2-花生四烯酰-sn-甘油-3-磷酸胆碱(PAPC)，是细胞膜的主要成分。它们接触活性氧会产生氧化磷脂，通过内皮激活和功能障碍，容易导致慢性炎症性疾病和代谢紊乱。尽管之前已经研究了氧化 PAPC (oxPAPC) 对内皮细胞的影响，但引起生物反应的潜在分子机制仍然很大程度上未知。在这里，我们利用 miRNA 分析、全局连续测序 (GRO-seq)、全基因组 NRF2 研究了 oxPAPC 功能的分子机制，特别重点研究人脐静脉内皮细胞 (HUVEC) 中 NRF2 调节的 microRNA (miRNA)结合模型以及带有 miRNA 过表达和沉默的 RNA 测序 (RNA-seq)。我们报道内皮活性的中央调节因子，KLF2（负责静止），PFKFB3（负责糖酵解），以及 VEGFA、FOXO1 和 MYC（负责生长和增殖），均受到转录因子 NRF2 和 NRF2 调节的 miR-106b∼25 簇成员 miR- 的调节。 93，在 HUVEC 中。从机制上讲，oxPAPC 被发现依赖于 NRF2 诱导糖酵解和增殖，并且 oxPAPC 依赖的 miR-106b∼25 簇诱导是由 NRF2 介导的。此外，在NRF2、miR-93和健康内皮的重要调节因子之间建立了几个调节环路，共同意味着NRF2与miR-93一起控制静止和增殖内皮状态之间的转换。