Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

Holdt, Lesca M.; Stahringer, Anika; Sass, Kristina; Pichler, Garwin; Kulak, Nils A.; Wilfert, Wolfgang; Kohlmaier, Alexander; Herbst, Andreas; Northoff, Bernd H.; Nicolaou, Alexandros; Gäbel, Gábor; Beutner, Frank; Scholz, Markus; Thiery, Joachim; Musunuru, Kiran; Krohn, Knut; Mann, Matthias; Teupser, Daniel

doi:10.1038/ncomms12429

Cited by 909 publications

(851 citation statements)

References 72 publications

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“…cANRIL, which serves as a factor in atherosclerotic cardiovascular disease and is located on chromosome 9p21, induces cell apoptosis, inhibits cell proliferation and reduces atheroprotective effects [13]. Moreover, elevated cANRIL expression increased EC apoptosis in the coronary arteries of rats, but reduced cANRIL expression resulted in an opposite trend.…”

Section: Discussionmentioning

confidence: 99%

“…The lncRNA ANRIL participates in the replication of the genetic risk locus for coronary artery disease (CAD), and it is independently correlated with several forms of immune-mediated, metabolic disorders and coronary heart disease [11, 12]. Previous work has demonstrated that the lncRNA ANRIL, which is transcribed at the cardiovascular disease risk locus on chromosome 9p21, can form RNA circles [13]. Circular RNAs (cRNAs) are a special type of a stable, diverse and conserved noncoding RNAs in mammalian cells [14].…”

Section: Introductionmentioning

confidence: 99%

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Effect of Circular ANRIL on the Inflammatory Response of Vascular Endothelial Cells in a Rat Model of Coronary Atherosclerosis

Song

Wang

Xue

et al. 2017

Cell Physiol Biochem

103

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Background/Aims: This study aims to investigate the role of circular antisense non-coding RNA at the INK4 locus (cANRIL) in the inflammatory response of vascular endothelial cells (ECs) in a rat model of coronary atherosclerosis (AS). A rat model of AS was established with rats that were injected with a large dose of vitamin D₃ and fed a high-fat diet. Methods: Sixty Wistar rats were randomly assigned into control, model, empty vector, over-expressed cANRIL and low-expressed cANRIL groups (12 rats in each group). Sixteen weeks later, the ultrastructure of their coronary arteries was observed via transmission electron microscopy. Rat serum lipid levels were analyzed using an automatic biochemical analyzer, and their atherogenic index (AI) values were calculated. Hematoxylin and eosin staining was used to observe the endothelial morphology of rats. Additionally, rat EC apoptosis was tested via a TUNEL assay. Enzyme-linked immunosorbent assays (ELISAs) were applied to measure serum levels of interleukin-1 (IL-1), IL-6, matrix metalloproteinase-9 (MMP-9) and C-reactive protein (CRP). The cANRIL, Bax, bcl-2 and caspase-3 mRNA expression levels were measured with a quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression levels of Bax, bcl-2 and caspase-3 were detected using immunohistochemistry. Results: In the control group, ECs were closely arranged with normal structures, and there was no proliferation. In the model, empty vector and over-expressed cANRIL groups, some cells were not present, and atherosclerotic plaques and thrombi appeared. However, in the under-expressed cANRIL group, the cells had a normal structure. Compared with the model and empty vector groups, the levels of total cholesterol (CHOL), triglycerides (TGs), low density lipoprotein (LDL), IL-1, IL-6, MMP-9, CRP, cANRIL, Bax, and caspase-3, AI values, and rates of EC apoptosis decreased in the low-expressed cANRIL group, while HDL (high density lipoprotein) levels and mRNA and protein expression levels of bcl-2 were increased. The changes in expression levels in the over-expressed cANRIL group were the opposite of those in the low-expressed cANRIL group. Conclusions: Our study provides evidence that reduced cANRIL expression could prevent coronary AS by reducing vascular EC apoptosis and inflammatory factor expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Circular ANRIL on the Inflammatory Response of Vascular Endothelial Cells in a Rat Model of Coronary Atherosclerosis

Song

Wang

Xue

et al. 2017

Cell Physiol Biochem

103

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“…Moreover, circRNAs appear to be expressed in tissue-and developmental-stage-specific manners, which indicates that they function in many physiological and pathophysiological processes [6,7]. Similar to miRNAs and lncRNAs, researchers have also found that circRNAs are related to many diseases, such as atherosclerosis, nervous system disorders, and a variety of cancers [8][9][10][11]. circRNAs are stable in cells because they are resistant to exonucleases; thus, circRNAs may constitute ideal biomarkers for cancer diagnosis [12].…”

Section: Introductionmentioning

confidence: 99%

The Landscape of Circular RNA Expression Profiles in Papillary Thyroid Carcinoma Based on RNA Sequencing

Lan

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. However, the molecular mechanisms responsible for its tumorigenesis and progression remain largely unknown. Circular RNA (circRNA) is a novel type of noncoding RNA that can serve as an ideal biomarker due to its stability. Recent evidence suggests that circRNAs play important roles in tumorigenesis. This study aims to investigate circRNA expression profiles and their potential biological functions in PTC. Methods: High-throughput RNA sequencing was used to assess circRNA expression profiles in PTC, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate dysregulated circRNAs. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic value of circRNAs for PTC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to determine the biological functions of differentially expressed circRNAs. Bioinformatic analyses were applied to predict interactions between circRNAs and microRNAs (miRNAs), and a circRNA-miRNA-mRNA network was constructed using Cytoscape software. Results: We identified a number of differentially expressed circRNAs in PTC tissues compared with paired normal thyroid tissues, with chr5: 160757890-160763776–, chr12: 40696591-40697936+, chr7: 22330794-22357656-, and chr21: 16386665-16415895– being upregulated, and chr7: 91924203-91957214+, chr2: 179514891-179516047–, chr9: 16435553-16437522–, and chr22: 36006931-36007153– being downregulated. These findings were confirmed by qRT-PCR, and ROC curves indicated that they can serve as potential biomarkers for PTC. GO and KEGG pathway analyses showed that some of these circRNAs are related to cancers. Additionally, bioinformatic analyses revealed a potential competing-endogenous-RNA-regulating network among circRNAs, miRNAs, and mRNAs. Conclusions: Our study results depict the landscape of circRNA expression profiles in PTC and also provide potential biomarkers for PTC. Further functional and mechanistic studies of these circRNAs may improve our understanding of PTC tumorigenesis.

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“…An example is the circular RNA ANRIL (antisense noncoding RNA in the INK4 locus), which affects atherogenesis by acting as a scaffold to prevent ribosomal RNA function. 115 Although circular RNAs can be challenging to interrogate because they are not captured by poly-based sequencing methods, their study has filled a substantial gap in mechanisms orchestrating cardiovascular disease. 116 Thus, epigenetic modification is no longer a term that is restricted to DNA/chromatin interrogation.…”

Section: Knockout Mouse Generationmentioning

confidence: 99%

Long Noncoding RNA Discovery in Cardiovascular Disease

Sallam

Sandhu

Tontonoz

2018

Circulation Research

223

157

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Despite significant improvements during the past 3 decades, cardiovascular disease remains a leading worldwide health epidemic. The recent identification of a fascinating group of mediators known as long noncoding RNAs (lncRNAs) has provided a wealth of new biology to explore for cardiovascular risk mitigation. lncRNAs are expressed in a highly context-specific fashion, and multiple lines of evidence implicated them in diverse biological processes. Indeed, abnormalities of lncRNAs have been directly linked with human ailments, including cardiovascular biology and disease. Of particular interest to the cardiovascular research community, dysregulation in lncRNA regulatory circuits have been associated with cardiac pathological hypertrophy, vascular disease, cell fate programming and development, atherosclerosis, dyslipidemia, and metabolic syndrome. Although techniques in interrogating noncoding RNAs are rapidly evolving, a major challenge in studying lncRNAs remains navigating through multiple technical constraints. In this review, we provide a road map for lncRNA discovery and interrogation in biological systems relevant to cardiovascular disease and highlight approaches to decipher their modes of action.

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Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

Cited by 909 publications

References 72 publications

Effect of Circular ANRIL on the Inflammatory Response of Vascular Endothelial Cells in a Rat Model of Coronary Atherosclerosis

Effect of Circular ANRIL on the Inflammatory Response of Vascular Endothelial Cells in a Rat Model of Coronary Atherosclerosis

The Landscape of Circular RNA Expression Profiles in Papillary Thyroid Carcinoma Based on RNA Sequencing

Long Noncoding RNA Discovery in Cardiovascular Disease

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