Exploring the Multifaceted Biologically Relevant Roles of circRNAs: From Regulation, Translation to Biomarkers
Abstract
:1. Introduction
1.1. Methodologies for the Identification of circRNAs
1.2. circRNAs as miRNA Sponges
1.3. circRNA-Protein Interactions
1.4. Translatable circRNAs in Heart
1.5. circRNAs as Biomarkers for Cardiovascular Diseases
2. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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circRNA | Original Gene | miRNA(s) Sponged/mRNA Target | Number of miRNA Binding Sites | Disease/Biological Context | Biological Sample | circRNA Expression | miRNA Expression | Refs. |
---|---|---|---|---|---|---|---|---|
CDR1as | Cerebellar-degeneration-related protein 1 (CDR1) exons | miR-7/PARP and SP1 | 73 | MI | Mouse tissue and cardiomyocytes | Upregulated | Upregulated | [95] |
miR-7-5p/CAMK2D and CNN3 | 8 | Pulmonary hypertension (PH) | HPASMCs | Upregulated | Decreased | [100] | ||
miR-135a and b/HMOX1 | 1 | CHF-associated proliferation and apoptosis | CHF patient plasma, HCMs, and AC16 cell lines | Upregulated | Decreased | [99] | ||
CircHIPK3 | Homeodomain-interacting protein kinases (HIPK3) exon 2 | miR-106a-5p/MFN2 | 1 | Atherosclerosis | AS patient tissue, blood samples, and VSMC | Low expression | High expression | [107] |
miR-29a/IGF-1 and VEGF | 1 | MI | Mouse cardiac microvascular endothelial cells (CMVECs) | Upregulated | Upregulated | [104,105] | ||
miRNA-124-3p | 1 | Myocardial ischemia/reperfusion (IR) injury | HCM cells | Highly expressed | Negatively correlated with circRNA expression | [106] | ||
circNFIX | Nuclear Factor IX exon 2 | miR-214/Gsk3β | 3 | MI and cardiac regeneration | Mouse cardiomyocytes | Overexpressed in human, rats and mice | Negatively correlated with circRNA expression | [93] |
miR-145-5p/ATF3 | 1 | Cardiac hypertrophy | Patient plasma, neonatal mouse cardiomyocytes, mouse model | Downregulated | Negatively correlated with circRNA expression | [108] | ||
circSlc8a1 | Sodium–calcium exchanger gene Slc8a1 | miR-133a | 17 | Cardiac hypertrophy | Neonatal mouse cardiomyocytes | Unchanged during myocardial stress response, but overexpression leads to heart failure | Unaffected by circRNA expression and lower expression is associated with disease development | [114] |
circ_Lrp6 | Lipoprotein receptor 6 (Lrp6) | miR-145/ITGβ8, FASCIN, and KLF4 | At least 7 | VSMC growth, differentiation, and homeostasis | Mouse and human VSCMs | Enriched in VSMCs | Not correlated with circRNA expression | [94] |
circ-SNRK | Sucrose nonfermenting 1-related kinase (SNRK) exon 1-2 | miR-33/SNRK | 7 | Heart failure (HF) and associated hypoxia | Primary neonatal rat cardiomyocytes and HF rat model | Decreased | Unchanged | [113] |
Circ_BNIP3 (hsa_circ_0005972) | BCL2 interaction protein 3 (BNIP3) gene chr10:133784141-133787447 | miR-27a-3p/BNIP3, and 2 more unexplored miRNAs, miR-27b-3p and miR-128-3p | 1 | Hypoxia induced cardiac myocyte injury in ischemia and acute myocardial infarction (AMI) | Rat H9c2 cells | Upregulated | Downregulated while the other 2 were unchanged | [115] |
circTRRAP (hsa_circ_0081241) | Transformation/transcription domain-associated protein (TRRAP) gene chr7:98495363-98506585 | miR-761/MAP3K2 | 1 | Hypoxia induced cardiomyocyte injury in AMI | AC16 human cardiomyocytes | Overexpressed | Downregulated | [116] |
miR-370-3p/PAWR | 1 | Hypoxia induced cardiomyocyte injury in AMI | AC16 human cardiomyocytes | Upregulated | Negatively correlated | [117] | ||
CircRbms1 (mmu_circ_0001022, hsa_circ_0002136) | RNA binding motif single-stranded interacting protein 1 (Rbms1) gene | miR-742-3p/FOXO1 | 1 | Hypoxia induced cardiomyocyte injury in MI | MI mouse model tissues and mouse cardiomyocytes (H9c2) | Upregulated | Negatively correlated with circRNA expression | [118] |
miR-92a/BCL2L11 | 1 | AMI | MI mouse model and mouse cardiomyocytes (H9c2) | Overexpressed | Decreased | [119] | ||
miR-2355-3p/MST1 | 1 | I/R injury | H/R induced HCMs | Increased | Decreased | [120] | ||
circCHFR (circ_0029589) | Checkpoint with forkhead and ring finger domains (CHFR) gene chr12:133428203-133430159 | miR-15b-5p/GADD45G | 1 | Atherosclerosis | ox-LDL) induced HUVECs | Upregulated | Downregulated | [121] |
miR-424-5p/IGF2 | 1 | Atherosclerosis | Ox-LDL-treated human VSMCs | Upregulated | Downregulated | [122] | ||
miR-214-3p/Wnt3 | 1 | Atherosclerosis | Ox-LDL-treated human VSMCs | Upregulated | Negatively correlated | [123] | ||
miR-370/FOXO1 | 1 | Atherosclerosis | Ox-LDL-treated human VSMCs | Upregulated | Negatively correlated | [124] | ||
circArhgap12 | Rho GTPase activating protein 12 (ARHGAP12) gene exon 3 and exon 2 | miR-135a-5p/ADCY1, and 7 more miRNAs | 1 | Doxorubicin-induced cardiotoxicity | Mouse cardiomyocytes | Upregulated | Upregulated while 7 others were unchanged | [125] |
miR-630/EZH2 | 1 | Atherosclerosis | Mouse aortic smooth muscle cells (MASMCs) | Upregulated | miR-630 was negatively correlated and miR-610 was unchanged, but not used for sponging validation | [126] | ||
circSMOC1 | Modular calcium-binding protein 1 (SMOC1) gene exon 4 to exon 7 | miR-329-3p/PDHB | 1 | Pulmonary hypertension | Rat pulmonary artery smooth muscle cells | Downregulated | Unchanged | [127] |
circSirtuin1 or circSirt1 | Sirtuin 1 (SIRT1) exon 2 to exon-7 | miR-132/212/Sirt1 | 3 | Atherosclerosis | Human and rat arterial tissues and VSMCs | Low expression | Negatively correlated with circRNA expression | [128] |
miR-145-5p/Akt3 | 1 | Pulmonary hypertesion | Rat model for PH and Human PASMCs | Increased | Decreased | [110] | ||
circ-calm4 | Calmodulin 4 gene single exon | miR-337-3p/Myosin 10 | 17 | Pulmonary hypertension | Mouse pulmonary artery smooth muscle cells (PASMCs) | Upregulated | Downregulated | [112] |
miR-124-3p/PDCD6 | 2 | Pulmonary hypertension and vascular smooth muscle cell pyroptosis | PH mouse model and cultured pulmonary artery smooth muscle cells (PASMCs) | Upregulated | Downregulated | [111] | ||
circ_0010283 | Ubiquitin protein ligase E3 component n-recognin 4 (UBR4) gene chr1:19449326-19480433 | miR-370-3p/HMGB1 | 1 | Atherosclerosis | ox-LDL-induced HVSMCs | Upregulated | Downregulated | [129] |
circ-BPTF | Bromodomain PHD finger transcription factor (BPTF) gene exons 21 to 27 | miR-486-5p/CEMIP | 2 | Chronic obstructive pulmonary disease (COPD) | Human PASMCs | Upregulated | Downregulated | [130] |
circ-SWT1 (hsa_circ_0015677) | SWT1 RNA endoribonuclease homolog gene chr1: 185,153,374–185,200,840 | miR-192-5p/SOD2 | 2 | H2O2 induced apoptosis in AMI | Human AC16 cardiomyocytes | Downregulated | Upregulated | [131] |
circPHKA2 (hsa_circ_0090002) | phosphorylase kinase regulatory subunit alpha 2 (PHKA2) exons 2-29 | miR-574-5p/SOD2 | 2 | Acute ischemic stroke (AIS) | Patient blood, immortalized HBMECs | Downregulated | Upregulated | [132] |
circRNA_101237 | Cyclin-dependent kinase 8 (CDK8) gene exon 10 to exon 12 | let-7a-5p/IGF2BP3 | 2 | Anoxia/reoxygenation (A/R) induced cardiomyocyte death | A/R-treated mouse cardiomyocytes | Upregulated | Unaffected by circRNA expression | [133] |
circNRG-1 | Neuregulin-1 (NRG-1) gene | miR-193b-5p/NRG-1 | 3 | VSMC proliferation in vascular remodeling | Ang-II-treated mouse aortic smooth muscle cells (MASMCs) | Downregulated | Upregulated | [134] |
circRNA-Protein Interaction | circRNA | Interacting Protein | Nature of Interaction | Consequence of Interaction | Cell/Tissue | Physiology/Disease | Refs. |
---|---|---|---|---|---|---|---|
Regulating mRNA stability/expression | Circ-USP9x | ElF4A3 | Direct binding in the cytoplasm | Increased stability of GSDMD mRNA, leading to AS-associated pyropstosis | Ox-LDL treated HUVECs | Atherosclerosis | [137] |
CircZNF609 | YTHDF3 | Direct binding in the cytoplasm | Competitive binding with YAP mRNA to YTHDF3 and modulation of YAP expression to promote heart repair | AC16 human cardiomyocyte | Cardiac repair | [149] | |
Autophagy-related circular RNA (ACR mmu_circRNA_006636) | Dnmt3B | Direct binding | Inhibition of DNA methylation of Pink1 promoter, thus blocking the binding of Dnmt3B to suppress cardiac autophagy and I/R injury | Mouse cardiomyocytes | I/R injury of cardiomyocytes in MI | [150] | |
CircSMOC1 | PTBP1 | Direct binding in the nucleus | Competitive inhibition of pyruvate kinase M 1 (PKM1) pre-mRNA to promote the expression of PKM2 and regulate glycolysis | Rat pulmonary artery smooth muscle cells | Pulmonary vascular remodeling and arterial hypertension | [127] | |
Circ-TLR4 | FUS | Direct binding in the cytoplasm | Promotion of TLR4 mRNA stability in the disease | Human cardiomyocytes | Cardiac hypertrophy | [151] | |
CircFndc3b | FUS | Unclear interaction | Interaction with FUS is suggested to regulate FUS mRNA stability and regulate VEGF expression | Rat cardiomyocytes and mouse cardiac endothelial cells | Cardiac repair | [152] | |
Circ_SMAD7 (hsa_circ_0000848) | ELAVL1 | Unclear interaction | Increased stability of the MI suppressor SMAD7 mRNA, reducing disease effects | HPC-CMs and H9c2 cardiomyocytes | Apoptosis of hypoxia induced cardiomyocytes | [153] | |
CircFoxo3 | KAT7 | Unclear interaction | Suppressing the expression of MI associated factor, HMGB1 by inhibiting KAT7 and reducing the enrichment of H3 lysine acetylation and RNA pol II at the HMGB1 promoter | MI rat model and H9c2 rat cardiomyocytes | MI induced Myocardial injury | [147] | |
CircHIPK3 | PTEN | Unclear interaction | Decrease in the levels of PTEN mRNA and protein-suppressing cardiomyocyte apoptosis | AC16 human cardiomyocytes | High-glucose-induced cell apoptosis in diabetic cardiomyopathy | [135] | |
Expression regulation of circRNA by protein | Circ_0029589 (circCHFR) | IFN regulatory factor 1 (IRF1) | m6A modification | Promotion of m6A modifications to the circRNA by IRF1 via m6A methyltransferase METTL3 to downregulate the circRNA in the disease | Human-PBMC-derived macrophages from CAD patients | Acute coronary syndrome and Atherosclerosis | [154] |
Circ_BNIP3 (hsa_circ_0005972) | ElF4A3 | Binding to the parent mRNA | ElF4A3 bound to the upstream site of BNIP3 mRNA to induce circBNIP3 expression | Rat H9c2 cells | Hypoxia induced cardiomyocyte injury | [115] | |
circSNRK | NOVA alternative splicing regulator 1 | Direct binding to flanking introns of pre-circ-SNRK | Inducing circSNRK expression by promoting alternative splicing mediated by the competitive binding of a 55 kDa SNRK peptide | Primary neonatal rat cardiomyocytes and HF rat model | HF and associated hypoxia | [113] | |
Nuclear translocation or Cytoplasmic sequestration of protein | circHelz | YAP1 | Direct binding in the cytoplasm | Promotion of nuclear localization of YAP1 to promote growth and proliferation | Mouse CFs | Cardiac Fibrosis | [143] |
Circ-JA760602 | EGR1 and E2F1 | Direct binding in the cytoplasm | Inhibited nuclear translocation of EGR1 and E2F1 to suppress transcriptional activation of BCL2 | AC16 human cardiomyocytes | Hypoxia induced AMI and associated apoptosis | [138] | |
Necroptosis-associated circRNA (CNEACR) | Histone deacetylases 7 (HDAC7) | Direct binding in the cytoplasm | Restriction of the nuclear import of HDAC7 to attenuate FoxA2 transcription and prevent myocardial damage | Mouse cardiomyocytes | Necroptotic death and I/R injury of cardiomyocytes in MI | [155] | |
CircEsyt2 | PolyC-binding protein 1 (PCBP1) | Direct binding in the cytoplasm | Inhibition of nuclear translocation of PCBP1 to regulate p53 pre-mRNA splicing | Human aortic smooth muscle cells (HASMCs) and mouse VSMCs | Arterial remodeling | [156] | |
Circ-Sirt1 | Cardiac myosin binding protein-C (c-Myc) | Direct binding in the cytoplasm | Promotion of cytoplasmic sequestration of VSCM-proliferation-associated c-Myc to prevent PDGF-BB-induced binding of c-Myc to the cyclin B1 promoter | Rat VSMCs | Restenosis and neointimal formation after injury | [157] | |
Protein stability | Ferroptosis-associated circRNA (circFEACR) | NAMPT | Direct binding in the cytoplasm | Increased half-life and stability of NAMPT following cycloheximide treatment without affecting mRNA levels | Mouse cardiomyocytes | Ferroptosis inhibition in myocardial I/R injury | [158] |
Protein degradation | CDR1as | MST1 | Unclear interaction | Increase in ubiquitination and subsequent degradation of MST1, thus activating Hippo-signaling pathway and promoting apoptosis of cardiomyocytes | Mouse cardiomyocytes | Diabetic cardiomyopathy | [140] |
circNFIX | Y-box binding protein 1 (Ybx1) | Direct binding in the cytoplasm | Promotion of Ybx1 degradation through ubiquitinoylation by competing with E3 ubiquitin ligase Nedd41, influencing the interaction between Ybx1 and Nedd4l | Mouse cardiomyocytes | Cardiac regeneration | [93] | |
Protein phosphorylation | CircFoxo3 | Foxo3 | Direct binding | Inhibition of Foxo3 protein phosphorylation at Ser253 via AKT and regulating I/R injury | HL-1 mouse atrial cardiomyocytes | Transplantation induced I/R injury | [139] |
Protein complex formation/Protein scaffolds | circYap (hsa_circ_0002320) | Tropomyosin-4 and Gamma-Actin | Direct binding | Enhancing the binding between TPM4 and ACTG to form complexes to inhibit actin polymerization | AC16 human cardiomyocytes and pressure-overload mouse model | Cardiac fibrosis | [141] |
CircHIPK3 | HuR and β-TrCP | Direct binding in the cytoplasm | Post-transcriptional regulation and localization of HuR, increasing its association with E3 ubiquitin ligase β-TrCP, promoting its degradation and cardiac senescence | CircHIPK3 KO mouse and mouse cardiomyocytes | Cardiac senescence and aging | [144] | |
cZNF292/cZfp292 | Syndesmos (SDOS) | Direct binding | Enhancing the interaction between SDC4 and SDOS, thus influencing endothelial cell flow response | Mouse-model-derived aortic endothelium and retinal blood vessel and HUVECs | Endothelial cell morphology | [159] | |
Mitochondrial recruitment of protein | circSamd4 | Vcp protein | Direct binding near the mitochondria | Promotion of mitochondrial localization of Vcp to repress Vdac1 and reactive oxygen species | Mouse fetal and neonatal cardiomyocytes | Cardiac repair and regeneration | [142] |
Transcriptional recruitment of protein | circ-RCCD | YY1 transcription factor | Direct binding to YY1 and MyD88 in the cytoplasm | Promoting nuclear localization of YY1 to MyD88 promoter to inhibit its expression and facilitate cell differentiation | Mouse cardiac tissues and cardiomyocyte | Heart development and cardiomyocyte differentiation | [160] |
Multifaceted functionality | CircKrt4 | Transcriptional activator protein Pur-alpha (Pura) | Direct binding in the nucleus and cytoplasm | Regulation of endothelial-to-mesenchymal transition by modulating the interaction between Pura and N-cadherin | Mouse pulmonary artery endothelial cell (PAEC) | Pulmonary hypertension | [148] |
Glycerol kinase (Glpk) | Direct binding in the nucleus and cytoplasm | Regulating the mitochondrial translocation of Glpk | |||||
RNA-binding-motif protein 25 (RBM25) | Binding to Krt4 pre-mRNA | Promoting alternative splicing and cyclization of Krt4 gene, thereby inducing circKrt4 expression |
circRNA | Translated Product | Product Size | Translation Mechanism | Cardiovascular Disease/Physiology | Cell/Tissue/Location | Functional Importance | Refs. |
---|---|---|---|---|---|---|---|
circNlgn | Nlgn173 | 173aa | Unclear | Cardiac remodeling and cardiac fibrosis | AC16 human cardiomyocytes, Mouse primary cardiomyocytes, CFs and transgenic mouse model | CF growth and cardiomyocyte survival | [164,173] |
circ_0036176 | Myo9a-208 | 208aa | IRES | Cardiac remodeling | Human Ac16 cardiomyocytes | Inhibition of CF proliferation through the suppression of cyclin/Rb pathway | [165] |
circFNDC3B | circFNDC3B-218aa | 218aa | IRES | Unknown | Human CC cell lines | Colon cancer cell proliferation, migration, invasion and epithelial to mesenchymal transition | [152,172] |
CircZNF609 | ZNF609-250aa | 250aa | m6A modification/IRES | Unknown | Mouse and human myoblasts, HeLa, HEK293T | Regulation of myoblast proliferation and ischemic AKI | [179,182,184] |
circNPHP4 | - | - | Possible IRES | Coronary heart atherosclerotic disease | HCAECs | Unknown | [188] |
circ_Lrp6 | - | - | ORF detected | Vascular smooth muscle cell activity. | Human VSMCs | Regulation of VSMC activity | [94] |
CDR1as | - | - | Suggested | Unknown | Human heart | Unknown | [168] |
circRNA | Disease/Physiology | Cell/Tissue/Location | Expression | Function | Refs. |
---|---|---|---|---|---|
circRNA MICRA | LV dysfunction in MI | Human peripheral blood | Low expression | Uncharacterized | [198] |
circ 81906-RYR2 | AF | Left atrial appendage | Upregulated | Uncharacterized | [199] |
hsa_circ_0006314 and hsa_circ_0055387 | POAF | Whole blood | Upregulated | Uncharacterized | [200] |
circNFAT5 | Cardiac arrest | Whole blood | Upregulated | Uncharacterized | [201] |
hsa_circ_0000437 | Rheumatic valvular heart disease (RVHD) | RVHD plasma samples. | Higher expression | Promotion of cell proliferation and migration, inhibition of apoptosis | [207] |
CircSLC8A1 | Sudden cardiac death (SCD) caused by acute ischemic heart disease (IHD) | IHD rat and H9c2 cell models | Upregulated | Regulation of I/R injury and cardiomyocyte apoptosis | [109] |
circNFIX | Elevated at an early stage of ischemia and later downregulated | Cardiomyocyte apoptosis | |||
cZNF292 | Acute MI | Whole blood, HUVECs, and hESC-CM | Upregulated | Regulation of HUVEC AND hESC-CM apoptosis | [208] |
circSMARCA5 (hsa_circ_0001445) | Coronary heart disease (CHD) | Peripheral blood leukocytes | Downregulated | Implicated interaction with several miRNAs | [209] |
Atherosclerosis | Ox-LDL-treated HUVECs | Downregulated | SRSF1/β–catenin pathway influencing cell proliferation | [210] | |
circCCDC9 | Ischemic stroke and I/R injury | Transient middle cerebral artery occlusion (tMCAO) mice model | Decreased | Notch signaling pathway | [211] |
circNPHP4 | Coronary heart atherosclerotic disease | CAD-related monocytes | Upregulated | Heterogeneous cell adhesion of coronary artery endothelial cells | [188] |
circFoxO1 | Myopic choroidal vascular dysfunction | RF/6A cells | Upregulated | Inhibition of endothelial effects of angiogenesis | [212] |
circFoxo3 | Radiation-induced cardiotoxicity and heart damage | AC16 human cardiomyocytes | Upregulated | Protection against cardiotoxicity induced by radiation | [213] |
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Hoque, P.; Romero, B.; Akins, R.E.; Batish, M. Exploring the Multifaceted Biologically Relevant Roles of circRNAs: From Regulation, Translation to Biomarkers. Cells 2023, 12, 2813. https://doi.org/10.3390/cells12242813
Hoque P, Romero B, Akins RE, Batish M. Exploring the Multifaceted Biologically Relevant Roles of circRNAs: From Regulation, Translation to Biomarkers. Cells. 2023; 12(24):2813. https://doi.org/10.3390/cells12242813
Chicago/Turabian StyleHoque, Parsa, Brigette Romero, Robert E Akins, and Mona Batish. 2023. "Exploring the Multifaceted Biologically Relevant Roles of circRNAs: From Regulation, Translation to Biomarkers" Cells 12, no. 24: 2813. https://doi.org/10.3390/cells12242813