Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress

Quiles, Justin M.; Pepin, Mark E; Sunny, Sini; Shelar, Sandeep; Challa, Anil K.; Dalley, Brian; Hoidal, John R.; Pogwizd, Steven M.; Wende, Adam R.; Rajasekaran, Namakkal S.

doi:10.1038/s41598-021-90583-y

Cited by 17 publications

(11 citation statements)

References 57 publications

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“…Multifaceted interactions between "seed overlap" miRNAs and lipid-associated SNPs may be associated with transcriptional mechanisms controlling these miRNAs in a modular manner. Although the mechanisms underlying the coordinated downregulation of miR-128 and miR-148a in SLE are unclear, miR-148a and miR-128-2 are proposed to be transcriptional targets of Nrf2, a key regulator of cellular response to oxidized phospholipids and antioxidant response, in endothelial cells and heart [48,49]. In line with these reports, Nrf2 has been reported to suppress lupus nephritis through inhibition of oxidative injury and the NF-κB-mediated inflammatory response in mice [50][51][52].…”

Section: Discussionmentioning

confidence: 99%

Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis

et al. 2022

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Background Combinatorial gene regulation by multiple microRNAs (miRNAs) is widespread and closely spaced target sites often act cooperatively to achieve stronger repression (“neighborhood” miRNA cotargeting). While miRNA cotarget sites are suggested to be more conserved and implicated in developmental control, the pathological significance of miRNA cotargeting remains elusive. Results Here, we report the pathogenic impacts of combinatorial miRNA regulation on inflammation in systemic lupus erythematosus (SLE). In the SLE mouse model, we identified the downregulation of two miRNAs, miR-128 and miR-148a, by TLR7 stimulation in plasmacytoid dendritic cells. Functional analyses using human cell lines demonstrated that miR-128 and miR-148a additively target KLF4 via extensively overlapping target sites (“seed overlap” miRNA cotargeting) and suppress the inflammatory responses. At the transcriptome level, “seed overlap” miRNA cotargeting increases susceptibility to downregulation by two miRNAs, consistent with additive but not cooperative recruitment of two miRNAs. Systematic characterization further revealed that extensive “seed overlap” is a prevalent feature among broadly conserved miRNAs. Highly conserved target sites of broadly conserved miRNAs are largely divided into two classes—those conserved among eutherian mammals and from human to Coelacanth, and the latter, including KLF4-cotargeting sites, has a stronger association with both “seed overlap” and “neighborhood” miRNA cotargeting. Furthermore, a deeply conserved miRNA target class has a higher probability of haplo-insufficient genes. Conclusions Our study collectively suggests the complexity of distinct modes of miRNA cotargeting and the importance of their perturbations in human diseases.

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Section: Discussionmentioning

confidence: 99%

Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis

et al. 2022

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“…Heart rate, ECG signals and respiration were recorded. Parasternal long-axis-M mode images were analyzed for cardiac function using Vevo lab 3.1 software [ 21 , 22 , 23 ].…”

Section: Methodsmentioning

confidence: 99%

Transgenic Expression of Nrf2 Induces a Pro-Reductive Stress and Adaptive Cardiac Remodeling in the Mouse

Jyothidasan

Sunny

Murugesan

et al. 2022

Genes

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Nuclear factor, erythroid 2 like 2 (Nfe2l2 or Nrf2), is a transcription factor that protects cells by maintaining a homeostatic redox state during stress. The constitutive expression of Nrf2 (CaNrf2-TG) was previously shown to be pathological to the heart over time. We tested a hypothesis that the cardiac-specific expression of full length Nrf2 (mNrf2-TG) would moderately increase the basal antioxidant defense, triggering a pro-reductive environment leading to adaptive cardiac remodeling. Transgenic and non-transgenic (NTG) mice at 7–8 months of age were used to analyze the myocardial transcriptome, structure, and function. Next generation sequencing (NGS) for RNA profiling and qPCR-based validation of the NGS data, myocardial redox levels, and imaging (echocardiography) were performed. Transcriptomic analysis revealed that out of 14,665 identified mRNAs, 680 were differently expressed (DEG) in TG hearts. Of 680 DEGs, 429 were upregulated and 251 were downregulated significantly (FC > 2.0, p < 0.05). Gene set enrichment analysis revealed that the top altered pathways were (a) Nrf2 signaling, (b) glutathione metabolism and (c) ROS scavenging. A comparative analysis of the glutathione redox state in the hearts demonstrated significant differences between pro-reductive vs. hyper-reductive conditions (233 ± 36.7 and 380 ± 68.7 vs. 139 ± 8.6 µM/mg protein in mNrf2-TG and CaNrf2-TG vs. NTG). Genes involved in fetal development, hypertrophy, cytoskeletal rearrangement, histone deacetylases (HDACs), and GATA transcription factors were moderately increased in mNrf2-TG compared to CaNrf2-TG. Non-invasive echocardiography analysis revealed an increase in systolic function (ejection fraction) in mNrf2-TG, suggesting an adaptation, as opposed to pathological remodeling in CaNrf2-TG mice experiencing a hyper-reductive stress, leading to reduced survival (40% at 60 weeks). The effects of excess Nrf2-driven antioxidant transcriptome revealed a pro-reductive condition in the myocardium leading to an adaptive cardiac remodeling. While pre-conditioning the myocardial redox with excess antioxidants (i.e., pro-reductive state) could be beneficial against oxidative stress, a chronic pro-reductive environment in the myocardium might transition the adaptation to pathological remodeling.

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“…Nrf2 activity is regulated by a number of mechanisms, including the ubiquitin proteasome degradation system (UPS) [ 22 ], post-translational modifications [ 23 , 24 , 25 , 26 , 27 ], epigenetic regulation [ 28 , 29 ], microRNAs [ 30 , 31 ], and autoregulation [ 32 , 33 ]. The main regulatory pathway in response to agonists is the Keap1–Nrf2 UPS system ( Figure 1 ).…”

Section: Regulation Of Nrf2mentioning

confidence: 99%

Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases

Kim

Jeon

2022

IJMS

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Oxidative stress is a major component of cell damage and cell fat, and as such, it occupies a central position in the pathogenesis of metabolic disease. Nuclear factor-erythroid-derived 2-related factor 2 (Nrf2), a key transcription factor that coordinates expression of genes encoding antioxidant and detoxifying enzymes, is regulated primarily by Kelch-like ECH-associated protein 1 (Keap1). However, involvement of the Keap1–Nrf2 pathway in tissue and organism homeostasis goes far beyond protection from cellular stress. In this review, we focus on evidence for Nrf2 pathway dysfunction during development of several metabolic/inflammatory disorders, including diabetes and diabetic complications, obesity, inflammatory bowel disease, and autoimmune diseases. We also review the beneficial role of current molecular Nrf2 agonists and summarize their use in ongoing clinical trials. We conclude that Nrf2 is a promising target for regulation of numerous diseases associated with oxidative stress and inflammation. However, more studies are needed to explore the role of Nrf2 in the pathogenesis of metabolic/inflammatory diseases and to review safety implications before therapeutic use in clinical practice.

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Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress

Cited by 17 publications

References 57 publications

Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis

Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis

Transgenic Expression of Nrf2 Induces a Pro-Reductive Stress and Adaptive Cardiac Remodeling in the Mouse

Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases

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