The long non-coding RNA NRON promotes the development of cardiac hypertrophy in the murine heart

Hoepfner, Jeannine; Leonardy, Julia; Lu, Dongchao; Schmidt, Kevin; Hunkler, Hannah J.; Biss, Sinje; Foinquinos, Ariana; Ke, Xiaoyan; Kumarswamy, Regalla; Ramanujam, Deepak; Engelhardt, Stefan; Bär, Christian; Thum, Thomas

doi:10.1016/j.ymthe.2021.11.018

Cited by 16 publications

(14 citation statements)

References 31 publications

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“…Moreover, lncRNA H19 was found dysregulated in hypertrophic hearts and its modulation prevented LV remodeling by disrupting the pro-hypertrophic NFAT signaling ( 59 ). The lncRNA NRON exhibited pro-hypertrophic effects in the murine hearts, and was identified as a cardiac hypertrophy promoter in a recent study ( 60 ). An interesting mechanism by which lncRNAs can induce gene activation is by reducing the activity of endogenous gene inhibitors such as miRNAs.…”

Section: Non-coding Rnasmentioning

confidence: 99%

Epi-Drugs in Heart Failure

Gorica

Mohammed

Ambrosini

et al. 2022

Front. Cardiovasc. Med.

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Unveiling the secrets of genome’s flexibility does not only foster new research in the field, but also gives rise to the exploration and development of novel epigenetic-based therapies as an approach to alleviate disease phenotypes. A better understanding of chromatin biology (DNA/histone complexes) and non-coding RNAs (ncRNAs) has enabled the development of epigenetic drugs able to modulate transcriptional programs implicated in cardiovascular diseases. This particularly applies to heart failure, where epigenetic networks have shown to underpin several pathological features, such as left ventricular hypertrophy, fibrosis, cardiomyocyte apoptosis and microvascular dysfunction. Targeting epigenetic signals might represent a promising approach, especially in patients with heart failure with preserved ejection fraction (HFpEF), where prognosis remains poor and breakthrough therapies have yet to be approved. In this setting, epigenetics can be employed for the development of customized therapeutic approaches thus paving the way for personalized medicine. Even though the beneficial effects of epi-drugs are gaining attention, the number of epigenetic compounds used in the clinical practice remains low suggesting that more selective epi-drugs are needed. From DNA-methylation changes to non-coding RNAs, we can establish brand-new regulations for drug targets with the aim of restoring healthy epigenomes and transcriptional programs in the failing heart. In the present review, we bring the timeline of epi-drug discovery and development, thus highlighting the emerging role of epigenetic therapies in heart failure.

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Section: Non-coding Rnasmentioning

confidence: 99%

Epi-Drugs in Heart Failure

Gorica

Mohammed

Ambrosini

et al. 2022

Front. Cardiovasc. Med.

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“…Recent reports demonstrated that lncRNAs play an important role in the progression of several cardiovascular diseases, such as acute myocardial infarction, heart failure, and atrial fibrillation ( 15 – 17 ). In HCM, lncRNAs are verified to be involved in vital biological processes of myocardial fibrosis, myocardial hypertrophy, and atherosclerosis ( 18 , 19 ). For example, the overexpression of cardiomyocyte-specific non-coding repressor of factor of Nuclear factor of activated T-cells (NFAT) (NRON) exacerbated transverse aortic constriction (TAC)-induced hypertrophy in mice heart ( 19 ), and ROR sponges miR-133 to cause the re-expression of atrial natriuretic peptide and B-type natriuretic peptide, leading to the exacerbation of cardiac hypertrophy eventually ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

“…In HCM, lncRNAs are verified to be involved in vital biological processes of myocardial fibrosis, myocardial hypertrophy, and atherosclerosis ( 18 , 19 ). For example, the overexpression of cardiomyocyte-specific non-coding repressor of factor of Nuclear factor of activated T-cells (NFAT) (NRON) exacerbated transverse aortic constriction (TAC)-induced hypertrophy in mice heart ( 19 ), and ROR sponges miR-133 to cause the re-expression of atrial natriuretic peptide and B-type natriuretic peptide, leading to the exacerbation of cardiac hypertrophy eventually ( 20 ). However, the role of lncRNAs in the progression of HCM remains to be further explored.…”

Section: Introductionmentioning

confidence: 99%

Identification of key genes for hypertrophic cardiomyopathy using integrated network analysis of differential lncRNA and gene expression

Cao

Liu

2022

Front. Cardiovasc. Med.

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ObjectiveHypertrophic cardiomyopathy (HCM) is a complex heterogeneous heart disease. Recent reports found that long non-coding RNAs (lncRNAs) play an important role in the progression of cardiovascular diseases. The present study aimed to identify the novel lncRNAs and messenger RNAs (mRNAs) and determine the key pathways involved in HCM.MethodsThe lncRNA and mRNA sequencing datasets of GSE68316 and GSE130036 were downloaded from the Gene Expression Omnibus (GEO) database. An integrated co-expression network analysis was conducted to identify differentially expressed lncRNAs and differentially expressed mRNAs in patients with HCM. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were explored to identify the biological functions and signaling pathways of the co-expression network. Protein–protein interaction (PPI) and hub gene networks were constructed by using Cytoscape software. Plasma samples of patients with HCM and the GSE89714 dataset were used to validate the bioinformatics results.ResultsA total of 1,426 differentially expressed long non-coding RNAs (lncRNAs) and 1,715 differentially expressed mRNAs were obtained from GSE68316, of which 965 lncRNAs and 896 mRNAs were upregulated and 461 lncRNAs and 819 mRNAs were downregulated. A total of 469 differentially expressed lncRNAs and 2,407 differentially expressed mRNAs were screened from GSE130036, of which 183 lncRNAs and 1,283 mRNAs were upregulated and 286 lncRNAs and 1,124 mRNAs were downregulated. A co-expression network was constructed and contained 30 differentially expressed lncRNAs and 63 differentially expressed mRNAs, which were primarily involved in ‘G-protein beta/gamma-subunit complex binding,' ‘polyubiquitin modification-dependent protein binding,' ‘Apelin signaling pathway,' and ‘Wnt signaling pathway.' The 10 hub genes in the upregulated network [G Protein Subunit Alpha I2 (GNAI2), G Protein Subunit Alpha I1 (GNAI1), G Protein Subunit Alpha I3 (GNAI3), G Protein Subunit Gamma 2 (GNG2), G Protein Subunit Beta 1 (GNB1), G Protein Subunit Gamma 13 (GNG13), G Protein Subunit Gamma Transducin 1 (GNGT1), G Protein Subunit Gamma 12 (GNG12), AKT Serine/Threonine Kinase 1 (AKT1) and GNAS Complex Locus (GNAS)] and the 10 hub genes in the downregulated network [Nucleotide-Binding Oligomerization Domain Containing Protein 2 (NOD2), Receptor-Interacting Serine/Threonine Kinase 2 (RIPK2), Nucleotide-Binding Oligomerization Domain Containing Protein 1 (NOD1), Mitochondrial Antiviral Signaling Protein (MAVS), Autophagy Related 16-Like 1 (ATG16L1), Interferon Induced With Helicase C Domain 1 (IFIH1), Autophagy Related 5 (ATG5), TANK-Binding Kinase 1 (TBK1), Caspase Recruitment Domain Family Member 9 (CARD9), and von Willebrand factor (VWF)] were screened using cytoHubba. The expression of LA16c-312E8.2 and RP5-1160K1.3 in the plasma of patients with HCM was elevated, and the expression of the MIR22 host gene (MIR22HG) was decreased, which was consistent with our analysis, while the expression of LINC00324 and Small Nucleolar RNA Host Gene 12 (SNHG12) was not significantly different between the two groups. Verification analyses performed on GSE89714 showed the upregulated mRNAs of Chloride Voltage-Gated Channel 7 (CLCN7), N-Acetylglucosamine-1-Phosphate Transferase Subunit Gamma (GNPTG), Unk Like Zinc Finger (UNKL), Adenosine Monophosphate Deaminase 2 (AMPD2), GNAI3, WD Repeat Domain 81 (WDR81), and Serpin Family F Member 1 (SERPINF1) and downregulated mRNAs of TATA-Box Binding Protein Associated Factor 12 (TAF12) co-expressed with five crucial lncRNAs. Moreover, GNAI2, GNAI3, GNG12, and vWF were upregulated and GNAS was downregulated in the top 10 hub genes of upregulated and downregulated PPI networks.ConclusionThese findings from integrative biological analysis of lncRNA-mRNA co-expression networks explored the key genes and pathways and provide new insights into the understanding of the mechanism and discovering new therapeutic targets for HCM. Three differentially expressed pivotal lncRNAs (LA16c-312E8.2, RP5-1160K1.3, and MIR22HG) in the co-expression network may serve as biomarkers and intervention targets for the diagnosis and treatment of HCM.

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“…GapmeRs, which are the class of antisense oligonucleotides used to target lncExACT1 in this study, are highly effective in vivo because they can enter both the cytoplasm and nucleus, thereby enabling the efficient targeting of both cytoplasmic and nuclear RNA molecules (such as lncExACT1). Whereas the inhibition of several lncRNAs that are upregulated in response to pressure overload is sufficient to attenuate pathological remodeling and dysfunction in experimental mouse models (ie, Chast 5 , Chaer 6 , NRON 9 ), the silencing of lncExACT1 is the first known example to concomitantly promote cardiomyogenesis and physiological hypertrophy, indicating that it is a therapeutic target that warrants further detailed investigation. Future studies should aim to assess efficacy in additional heart failure models and large animal models as well as to study potential off-target effects and toxicity.…”

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confidence: 99%

“…Additional cardiac lncRNAs are dynamically regulated during the compensatory (hypertrophic) and decompensatory (heart failure) phases of TAC-induced pressure-overload including H19 (H19 imprinted maternally expressed transcript) 8 and NRON (noncoding repressor of NFAT [nuclear factor of activated T cells]). 9 These studies have shown that lncRNAs can serve as therapeutic targets, evidenced by the cardioprotection observed in mouse models of TAC in response to targeted knockdown or deletion of specific lncRNAs (Chast, 5 Chaer, 6 NRON 9 ) or via overexpression (Mhrt, 7 H19 8 ).…”

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confidence: 99%