NRF2 is a key regulator of endothelial microRNA expression under proatherogenic stimuli

Abstract

Aims 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 (HUVECs) and aortic endothelial cells (HAECs) with a special focus on miRNAs. Methods and results 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 upregulated transcripts and transcriptional initiation represent 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 expression. 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. Conclusions 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. Translational Perspective Our analysis provides deeper understanding of the transcriptional regulation of miRNAs and their target genes that could regulate the proatherogenic effects of oxidized phospholipids in endothelial cells. We further characterize the role of miR-21-5p and miR-100-5p in regulating the VEGF pathway upon proatherogenic stimuli. We demonstrate that exosomal levels of both miRNAs obtained from pericardial fluid of cardiovascular disease patients are correlated with disease severity. Thus, future studies should determine the utility of miR-21-5p and miR-100-5p for the diagnosis of cardiovascular disease.

Extracellular Vesicles Derived From Human Umbilical Cord Mesenchymal Stem Cells Protect Against DOX-Induced Heart Failure Through the miR-100-5p/NOX4 Pathway

“…MiR-100-5p is believed to have anti-atherosclerotic effects because it inhibits the proliferation of endothelial cells and migration of blood vessels and smooth muscle cells ( Shoeibi, 2020 ). In a mouse model of atherosclerosis, the expression of miR-100-5p can improve endothelial function, weaken atherosclerosis, and reduce plaque area ( Linna-Kuosmanen et al, 2020 ). Further studies indicate that downregulation of miR-100-5p activates the VEGFA/MYC pathway, which leads to increased endothelial cell metabolism, proliferation, and angiogenesis, thereby promoting angiogenesis ( Pankratz et al, 2018 ).…”

Downregulation of microRNA-512-3p enhances the viability and suppresses the apoptosis of vascular endothelial cells, alleviates autophagy and endoplasmic reticulum stress as well as represses atherosclerotic lesions in atherosclerosis by adjusting spliced/unspliced ratio of X-box binding protein 1 (XBP-1S/XBP-1U)

“…Recent researches have identified that miRNAs are attracting more attention due to their key regulatory roles in the pathogenesis of AS [ 10 , 11 ]. For example, literature has reported that miR-590 could inhibit atherosclerotic lesion in the in vivo models of AS and facilitate the proliferation and suppress the apoptosis of ox-LDL-treated human aortic endothelial cells [ 23 ].…”

“…It can regulate gene expression at the posttranscription level and play an important role in human growth, development, physiology, and pathology [ 9 ]. Numerous researches have reported that miRNAs are involved in almost all steps of AS, including the injury and dysfunction of endothelial cells and vascular smooth muscle cells [ 10 , 11 ]. Liu et al [ 12 ] proved that miR-130a was up-regulated in AS mice, and miR-130a knockdown suppressed the inflammation of LPS-induced human umbilical vein endothelial cells (HUVECs) in an in vitro model of AS.…”

Stool microRNA profiles reflect different dietary and gut microbiome patterns in healthy individuals

“…80 We can hypothesise that miR-425-3p and miR-4277 may form a negative feedback loop on the increasing level of this nutrient in VT/VN. Interestingly, miR-425-3p was included in the list of miRNAs regulated by the activity of nuclear factor erythroid 2-related factor 2 (Nrf2), 81 a transcription factor involved in the regulation of metabolism downstream of nutrient-sensing pathways, whose activity is pivotal for the gastrointestinal tract development and maintenance. 82 MiRNAs are present in all eukaryotes: an intriguing aspect is that they could potentially 'traverse' from plants to animals through food via the gastrointestinal tract and access host cellular targets, where they could work as bioactive compounds and influence recipients' physio-pathological conditions.…”