A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
Cardiovasc Res. 2021 Apr 23;117(5):1339-1357. doi: 10.1093/cvr/cvaa219.
Oxidized phospholipids and microRNAs (miRNAs) are increasingly recognized to play a role in endothelial dysfunction driving atherosclerosis. NRF2 transcription factor is one of the key mediators of the effects of oxidized phospholipids, but the gene regulatory mechanisms underlying the process remain obscure. Here, we investigated the genome-wide effects of oxidized phospholipids on transcriptional gene regulation in human umbilical vein endothelial cells and aortic endothelial cells with a special focus on miRNAs.
We integrated data from HiC, ChIP-seq, ATAC-seq, GRO-seq, miRNA-seq, and RNA-seq to provide deeper understanding of the transcriptional mechanisms driven by NRF2 in response to oxidized phospholipids. We demonstrate that presence of NRF2 motif and its binding is more prominent in the vicinity of up-regulated transcripts and transcriptional initiation represents the most likely mechanism of action. We further identified NRF2 as a novel regulator of over 100 endothelial pri-miRNAs. Among these, we characterize two hub miRNAs miR-21-5p and miR-100-5p and demonstrate their opposing roles on mTOR, VEGFA, HIF1A, and MYC expressions. Finally, we provide evidence that the levels of miR-21-5p and miR-100-5p in exosomes are increased upon senescence and exhibit a trend to correlate with the severity of coronary artery disease.
Altogether, our analysis provides an integrative view into the regulation of transcription and miRNA function that could mediate the proatherogenic effects of oxidized phospholipids in endothelial cells.
氧化磷脂和 microRNAs（miRNAs）在驱动动脉粥样硬化的内皮功能障碍中发挥作用的作用日益受到关注。NRF2 转录因子是氧化磷脂作用的关键介质之一，但该过程的基因调控机制仍不清楚。在这里，我们研究了氧化磷脂对人脐静脉内皮细胞和主动脉内皮细胞转录基因调控的全基因组影响，特别关注了 miRNAs。
我们整合了来自 HiC、ChIP-seq、ATAC-seq、GRO-seq、miRNA-seq 和 RNA-seq 的数据，以提供对 NRF2 响应氧化磷脂驱动的转录机制的更深入理解。我们证明了 NRF2 基序的存在及其结合在上调转录物的附近更为突出，并且转录起始代表最可能的作用机制。我们进一步确定 NRF2 是超过 100 个内皮前 miRNA 的新型调节剂。在这些 miRNA 中，我们对两个 hub miRNA miR-21-5p 和 miR-100-5p 进行了表征，并证明了它们对 mTOR、VEGFA、HIF1A 和 MYC 表达的相反作用。最后，我们提供了证据表明，衰老时外泌体中 miR-21-5p 和 miR-100-5p 的水平增加，并表现出与冠状动脉疾病严重程度相关的趋势。
总的来说，我们的分析提供了对转录和 miRNA 功能调节的综合观点，这可能介导氧化磷脂在内皮细胞中的促动脉粥样硬化作用。
