Circle the Cardiac Remodeling With circRNAs

Yang, Tao; Long, Tianxin; Du, Tailai; Chen, Yili; Dong, Yugang; Huang, Zhan-Peng

doi:10.3389/fcvm.2021.702586

Cited by 9 publications

(4 citation statements)

References 144 publications

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“…CircSLC8A1, which is enriched in cardiomyocytes, was reported as the most abundant circRNA in the human heart 58 . CircRNAs are also implicated as potential candidates for the treatment of cardiac fibrosis 27,59,60 . A recent study reported 662 circRNA-miRNA-mRNA interactions in heart failure patients 61 .…”

Section: Discussionmentioning

confidence: 99%

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circRNA-miRNA-mRNA networks reveal a proangiogenic action of circNPHP1 in human ischemic heart disease

Anwar,

Sarkar,

Ford

et al. 2024

Preprint

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BackgroundIschemic heart disease (IHD) is characterized by insufficient myocardial blood flow and aggravated by diabetes. IHD is often treated by coronary revascularization. Complementary therapies that increase the microvascular flow by promoting endothelial homeostasis and repair are still lacking and require the identification of new therapeutic targets. The expression of protein coding genes is regulated by multimodal interactions between different classes of non-coding RNAs. This study aimed to 1) unravel circular RNA (circRNA) -microRNA (miRNA) - messenger RNA (mRNA) networks across the human ischemic and control hearts; 2) identify and functionally test the sub-network with highest potential to control endothelial cell (EC) function.MethodsTwo intraoperative left ventricle biopsies were prospectively collected from type-2 diabetic and non-diabetic people with IHD and from a control group of non-IHD, non-diabetic patients (N=12 patients/group; ARCADIA study) and used for long transcriptome bulk-sequencing (circRNAs and mRNAs datasets) and small RNA-sequencing (miRNAs datasets). Differentially expressed (DE) RNAs were identified with a customized bioinformatics pipeline. We identified potential “sponging associations” between circRNAs and miRNAs and between miRNAs and mRNAs. Next, we created circRNA-miRNA-mRNA networks and retained the subnetworks where individual RNAs were expressed in ECs (using datasets from GEO database) and of potential relevance to endothelial function based on pathway analyses. Next, we screened top differentially expressed circRNAs in cultured ECs exposed to disease-mimic conditions vs control. The circRNA-miRNA sponging interactions of the top emerging circRNA candidate were confirmed after circRNA pulldown in ECs and the functional relevance was mechanistically tested in EC cell biology assays.ResultsWe created circRNA-miRNA-mRNA networks in IHD (with and without T2DM) and controls indicating distinct interactions in each. We unravelled a novel putative proangiogenic subnetwork, circNPHP1/miR-221-3p/VEGFA/BCL2, in the human ischemic heart specially enriched in IHD and T2DM. CircNPHP1 pull-down assay confirmed it’s binding to miR-221-3p. CircNPHP1 silencing in ECs reduced angiogenesis and decreased the expression of miR-221-3p target genes (VEGFA and BCL2). The proangiogenic action of circNPHP1/miR-221-3p was confirmed in ECs by combining circNPHP1 silencing with either miR-221-3p inhibition or overexpression in ECs.ConclusionsCircNPHP1 supports endothelial function through sponging of miR-221-3p in IHD and holds potential as novel therapeutic target in IHD.

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Section: Discussionmentioning

confidence: 99%

“…CircRNAs have been shown to regulate angiogenesis and EC response to ischemia/reperfusion (I/R) injury 26,27,28 . We have recently reviewed the RNA regulatory role of circRNAs in IHD and cardiac remodelling 29,30 .…”

Section: Introductionmentioning

confidence: 99%

circRNA-miRNA-mRNA networks reveal a proangiogenic action of circNPHP1 in human ischemic heart disease

Anwar,

Sarkar,

Ford

et al. 2024

Preprint

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“…As a non-coding RNA, circRNA was recently discovered. Previous studies have reported that circRNAs are associated with vascular dysfunction and multiple processes, such as vascular development, growth and remodelling ( 42 - 48 ). The present study performed a high-throughput transcriptome sequencing analysis of the PASMCs to investigate the differently expressed circRNAs and finally identified the upregulated circ-Grm1.…”

Section: Discussionmentioning

confidence: 99%

circ‑Grm1 promotes pulmonary artery smooth muscle cell proliferation and migration via suppression of GRM1 expression by FUS

et al. 2021

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Pulmonary arterial hypertension is a progressive and fatal disease. Recent studies suggest that circular RNA (circRNAs/circs) can regulate various biological processes, including cell proliferation. Therefore, it is possible that circRNA may have important roles in pulmonary artery smooth muscle cell proliferation in hypoxic pulmonary hypertension (HPH). The aim of the present study was to determine the role and mechanism of circRNA-glutamate metabotropic receptor 1 (circ-Grm1; mmu_circ_0001907) in pulmonary artery smooth muscle cell (PASMC) proliferation and migration in HPH. High-throughput transcriptome sequencing was used to screen circRNAs and targeted genes involved in HPH. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2-deoxyuridine and wound healing assays were employed to assess cell viability and migration. Reverse transcription-quantitative PCR and western blotting were used to detect target gene expression in different groups. Bioinformatical approaches were used to predict the interaction probabilities of circ-Grm1 and Grm1 with FUS RNA binding protein (FUS). The interactions of circ-Grm1, Grm1 and FUS were evaluated using RNA silencing and RNA immunoprecipitation assays. The results demonstrated that circ-Grm1 was upregulated in hypoxic PASMCs. Further experiments revealed that the knockdown of circ-Grm1 could suppress the proliferation and migration of hypoxic PASMCs. Transcriptome sequencing revealed that Grm1 could be the target gene of circ-Grm1. It was found that circ-Grm1 could competitively bind to FUS and consequently downregulate Grm1. Moreover, Grm1 could inhibit the function of circ-Grm1 by promoting the proliferative and migratory abilities of hypoxic PASMCs. The results also demonstrated that circ-Grm1 influenced the biological functions of PASMCs via the Rap1/ERK pathway by regulating Grm1. Overall, the current results suggested that circ-Grm1 was associated with HPH and promoted the proliferation and migration of PASMCs via suppression of Grm1 expression through FUS.

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“…It can participate in protein translation. 36 CirRNAs are widespread and diverse in eukaryotic cells, 37 but relatively stable in the cytoplasm. 38 CirRNAs can be co-transcribed and post-transcribed by a process of reverse splicing or head-tail circular splicing, in which the downstream exon splices in reverse order to the upstream exon.…”

Section: Epigenetic Regulatory Mechanismsmentioning

confidence: 99%

Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials

Shi

Zhang

Huang

et al. 2022

Sig Transduct Target Ther

157

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Epigenetics is closely related to cardiovascular diseases. Genome-wide linkage and association analyses and candidate gene approaches illustrate the multigenic complexity of cardiovascular disease. Several epigenetic mechanisms, such as DNA methylation, histone modification, and noncoding RNA, which are of importance for cardiovascular disease development and regression. Targeting epigenetic key enzymes, especially the DNA methyltransferases, histone methyltransferases, histone acetylases, histone deacetylases and their regulated target genes, could represent an attractive new route for the diagnosis and treatment of cardiovascular diseases. Herein, we summarize the knowledge on epigenetic history and essential regulatory mechanisms in cardiovascular diseases. Furthermore, we discuss the preclinical studies and drugs that are targeted these epigenetic key enzymes for cardiovascular diseases therapy. Finally, we conclude the clinical trials that are going to target some of these processes.

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Circle the Cardiac Remodeling With circRNAs

Cited by 9 publications

References 144 publications

circRNA-miRNA-mRNA networks reveal a proangiogenic action of circNPHP1 in human ischemic heart disease

circRNA-miRNA-mRNA networks reveal a proangiogenic action of circNPHP1 in human ischemic heart disease

circ‑Grm1 promotes pulmonary artery smooth muscle cell proliferation and migration via suppression of GRM1 expression by FUS

Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials

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