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Wang JN, Zhou YY, Yu YW, Chen J. Profiling and bioinformatics analyses of circular RNAs in myocardial ischemia/reperfusion injury model in mice. World J Cardiol 2025; 17:102147. [PMID: 39866220 PMCID: PMC11755133 DOI: 10.4330/wjc.v17.i1.102147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/23/2024] [Accepted: 12/19/2024] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Myocardial ischemia/reperfusion (I/R) injury, which is associated with high morbidity and mortality, is a main cause of unexpected myocardial injury after acute myocardial infarction. However, the underlying mechanism remains unclear. Circular RNAs (circRNAs), which are formed from protein-coding genes, can sequester microRNAs or proteins, modulate transcription and interfere with splicing. Authoritative studies suggest that circRNAs may play an important role in myocardial I/R injury. AIM To explore the role and mechanism of circRNAs in myocardial I/R injury. METHODS We constructed a myocardial I/R injury model using ligation of the left anterior descending coronary artery, and evaluated the success of the validated model using triphenyltetrazolium chloride and hematoxylin-eosin staining. Then, left ventricular samples from different groups were selected for mRNA-sequence, and differential gene screening was performed on the obtained results. The differentially obtained mRNAs were divided into up-regulated and down-regulated according to their expression levels, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis were performed, respectively. Then, the obtained circRNA and microRNA (miRNA) were paired for analysis, and the binding sites of miRNA and mRNA were virtual screened. Finally, the obtained circRNA, miRNA and mRNA were constructed by ceRNA mutual most useful network. RESULTS We used an RNA sequencing array to investigate the expression signatures of circRNAs in myocardial I/R injury using three samples from the I/R group and three samples from the sham group. A total of 142 upregulated and 121 downregulated circRNAs were found to be differentially expressed (fold change ≥ 2, P < 0.05). GO and KEGG functional analyses of these circRNAs were performed. GO analysis revealed that these circRNAs were involved mainly in cellular and intracellular processes. KEGG analysis demonstrated that 6 of the top 20 pathways were correlated with cell apoptosis. Furthermore, a circRNA-miRNA coexpression network and ceRNA network based on these genes were constructed, revealing that mmu-circ-0001452, mmu-circ-0001637, and mmu-circ-0000870 might be key regulators of myocardial I/R injury. CONCLUSION This research provides new insights into the mechanism of myocardial I/R, which mmu-circ-0001452, mmu-circ-0001637, and mmu-circ-0000870 are expected to be new therapeutic targets for myocardial I/R injury.
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Affiliation(s)
- Jiao-Ni Wang
- Department of Diagnostic Ultrasound and Echocardiography, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310002, Zhejiang Province, China
| | - Ying-Ying Zhou
- Department of Endocrinology, The Second Affliated and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Yong-Wei Yu
- Department of Critical Care Medicine, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China.
| | - Jun Chen
- Cardiac Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
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Wang L, Wang C, Sun Z, Du A, Shan F, Sun Z. Knockdown of Mmu-circ-0001380 Attenuates Myocardial Ischemia/Reperfusion Injury via Modulating miR-106b-5p/Phlpp2 Axis. J Cardiovasc Transl Res 2023; 16:1064-1077. [PMID: 37474690 DOI: 10.1007/s12265-023-10383-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 03/22/2023] [Indexed: 07/22/2023]
Abstract
Myocardial ischemia/reperfusion (MI/R) injury induces myocardial damage and dysfunction. Increasing evidence has confirmed that circular RNAs (circRNAs) play crucial roles in regulating MI/R. Mmu-circ-0001380 has identified to be highly expressed in myocardium of MI/R mouse model. However, its biological function and molecular mechanism in MI/R injury are still unclear. Here, we demonstrated that knockdown of cric-0001380 attenuated myocardial injury of MI/R mice. In vitro, silence of circ-0001380 significantly enhanced viability, and inhibited apoptosis and oxidative stress in HL-1 cells under oxygen-glucose deprivation/reoxygenation (OGD/R). Mmu-miR-106b-5p interacted with circ-0001380, and suppressed the expression of pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (Phlpp2). The miR-106b-5p/Phlpp2 axis mediated the effect of circ-0001380 on OGD/R-induced apoptosis through regulating the phosphorylation of p38, and further involved in regulating the viability and oxidative stress of HL-1 cells. In conclusion, circ-0001380 downregulation relieves MI/R injury via regulating the miR-106b-5p/Phlpp2 axis. The present study indicates that mmu-circ-0001380 exacerbates the myocardial ischemia/reperfusion injury through modulating the miR-106b-5p/Phlpp2 axis in vitro and in vivo.
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Affiliation(s)
- Li Wang
- Department of Cardiology, Dalian Municipal Central Hospital, No. 826, Xinan Road, Dalian, Liaoning, China.
| | - Chuanhe Wang
- Department of Cardiology, Shengjing Hospital of China Medical University, No. 39, Huaxiang Road, Shenyang, Liaoning, China
| | - Zhaoqing Sun
- Department of Cardiology, Shengjing Hospital of China Medical University, No. 39, Huaxiang Road, Shenyang, Liaoning, China
| | - Aolin Du
- Department of Cardiology, Shengjing Hospital of China Medical University, No. 39, Huaxiang Road, Shenyang, Liaoning, China
| | - Fei Shan
- Department of Cardiology, Shengjing Hospital of China Medical University, No. 39, Huaxiang Road, Shenyang, Liaoning, China
| | - Zhijun Sun
- Department of Cardiology, Shengjing Hospital of China Medical University, No. 39, Huaxiang Road, Shenyang, Liaoning, China.
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Zhou D, Dai Z, Ren M, Yang M. Adipose-Derived Stem Cells-Derived Exosomes with High Amounts of Circ_0001747 Alleviate Hypoxia/Reoxygenation-Induced Injury in Myocardial Cells by Targeting MiR-199b-3p/MCL1 Axis. Int Heart J 2022; 63:356-366. [PMID: 35354755 DOI: 10.1536/ihj.21-441] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Recent studies demonstrated that circular RNAs play important roles in exosome-mediated cardio-protective effects after acute myocardial infarction (AMI). A previous study reported that circ_0001747 level is down-regulated in mouse hypoxia/reoxygenation (H/R) injury model. However, its biological role and working mechanism in AMI remain largely unknown.Exosomes were isolated from the culture supernatant of adipose-derived stem cells (ADSCs) using an ExoQuick precipitation kit. We treated mouse myocardial cells HL-1 with H/R to explore the role of exosomal circ_0001747 in AMI pathology. Cell viability, proliferation, apoptosis, and inflammation were analyzed by Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine assay, flow cytometry, and enzyme-linked immunosorbent assay. Dual-luciferase reporter assay and RNA immunoprecipitation assay were conducted to confirm the interaction between microRNA-199b-3p (miR-199b-3p) and circ_0001747 or MCL1 apoptosis regulator, BCL2 family member (MCL1).H/R-induced HL-1 dysfunction was attenuated by the incubation of exosomes derived from ADSCs, especially the exosomes with high amounts of circ_0001747. Circ_0001747 directly targeted miR-199b-3p in HL-1 cells. miR-199b-3p overexpression partly overturned exosomal circ_0001747-mediated protective effects in H/R-induced HL-1 cells. MCL1 was a direct target of miR-199b-3p in HL-1 cells. miR-199b-3p silencing alleviated H/R-induced damage in HL-1 cells partly by up-regulating MCL1. Circ_0001747 can elevate the messenger RNA and protein levels of MCL1 by sequestering miR-199b-3p.Overall, these results indicated that ADSCs-derived exosomes with high amounts of circ_0001747 attenuated H/R-induced HL-1 dysfunction partly by targeting miR-199b-3p/MCL1 signaling.
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Affiliation(s)
- Duohui Zhou
- Department of Cardiology, The Lu'an Hospital Affiliated to Anhui Medical University, The Lu'an People's Hospital
| | - Zhongli Dai
- Department of Cardiology, The Lu'an Hospital Affiliated to Anhui Medical University, The Lu'an People's Hospital
| | - Mingde Ren
- Department of Cardiology, The Lu'an Hospital Affiliated to Anhui Medical University, The Lu'an People's Hospital
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Tan C, Li J, Yuan Z, Mu Y. Circular RNA ciRs-126 promotes hypoxia/reoxygenation cardiac injury possibly through miR-21. Thromb J 2022; 20:2. [PMID: 34983563 PMCID: PMC8725357 DOI: 10.1186/s12959-021-00355-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 12/03/2021] [Indexed: 01/06/2023] Open
Abstract
Background This study aimed to analyze the role of circular RNA ciRs-126 in hypoxia/reoxygenation cardiac injury (H/R). Methods Expression of ciRs-126 and miR-21 in plasma samples from patients with H/R and healthy controls was determined by RT-qPCR. Correlations were analyzed by linear regression. Overexpression of ciRs-126 and miR-21 was achieved in cardiomyocytes to explore their crosstalk. The roles of ciRs-126 and miR-21 in H/R-induced apoptosis of cardiomyocytes were analyzed using cell apoptosis assay. Results CiRs-126 was upregulated and miR-21 was downregulated in H/R patients. They were inversely correlated across plasma samples from H/R patients. In H/R cardiomyocytes, ciRs-126 was upregulated and miR-21 was downregulated. In cardiomyocytes, ciRs-126 overexpression decreased miR-21 level and reduced the inhibitory effects of miR-21 overexpression on H/R-induced cell apoptosis. Conclusions Circular RNA ciRs-126 may suppress miR-21 expression to promote H/R cardiac injury. Supplementary Information The online version contains supplementary material available at 10.1186/s12959-021-00355-x.
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Affiliation(s)
- Changming Tan
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, 410011, Changsha, Hunan, China.
| | - Jianming Li
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, 410011, Changsha, Hunan, China
| | - Zhaoshun Yuan
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, 410011, Changsha, Hunan, China
| | - Yongxin Mu
- Department of Medicine, University of California, La Jolla, CA, San Diego, USA
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Wang S, Cheng Z, Chen X, Lu G, Zhu X, Xu G. CircUBXN7 mitigates H/R-induced cell apoptosis and inflammatory response through the miR-622-MCL1 axis. Am J Transl Res 2021; 13:8711-8727. [PMID: 34539989 PMCID: PMC8430130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/09/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Hypoxia/reoxygenation (H/R)-mediated apoptosis and inflammation are major causes of tissue injury in acute myocardial infarction (AMI). Exploring the underlying mechanisms of cardiomyocyte injury induced by H/R is important for AMI treatment. Circular RNAs have been demonstrated to paly vital roles in the pathogenesis of AMI. Our study aimed to explore the function of circular RNA UBXN7 (circUBXN7) in regulating H/R-induced cardiomyocyte injury. METHODS H/R-treated H9c2 cells and a mouse model of AMI were used to investigate the function of circUBXN7 in H/R damage and AMI. The expressions of circUNXN7, miR-622 and MCL1 were analyzed by RT-qPCR. CCK-8 was used for examining cell viability. Cell apoptosis was evaluated with caspase 3 activity and Annexin V/PI staining. MCL1, Bax, Bcl-2 and cleaved-caspase 3 were examined with western blot. ELISA was used to examine the secretion of IL-6, TNF-α and IL-1β. RESULTS CircUBXN7 was downregulated in patients and mice with AMI, as well as in H/R-treated cells. Overexpression of circUBXN7 mitigated H/R-mediated apoptosis and secretion of inflammatory factors including IL-6, TNF-α and IL-1β. CircUBXN7 suppressed cell apoptosis and inflammatory reaction induced by H/R via targeting miR-622. MiR-622 targeted MCL1 to restrain its expression in H9c2 cells. Knockdown of MCL1 abrogated circUBXN7-mediated alleviation of apoptosis and inflammation after H/R treatment. CONCLUSION CircUBXN7 mitigates cardiomyocyte apoptosis and inflammatory reaction in H/R injury by targeting miR-622 and maintaining MCL1 expression. Our study provides novel potential therapeutic targets for AMI treatment.
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Affiliation(s)
- Sheng Wang
- Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, Heart Center of He'nan Provincial People's Hospital Zhengzhou, He'nan Province, China
| | - Zhaoyun Cheng
- Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, Heart Center of He'nan Provincial People's Hospital Zhengzhou, He'nan Province, China
| | - Xianjie Chen
- Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, Heart Center of He'nan Provincial People's Hospital Zhengzhou, He'nan Province, China
| | - Guoqing Lu
- Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, Heart Center of He'nan Provincial People's Hospital Zhengzhou, He'nan Province, China
| | - Xiliang Zhu
- Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, Heart Center of He'nan Provincial People's Hospital Zhengzhou, He'nan Province, China
| | - Gaojun Xu
- Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, Heart Center of He'nan Provincial People's Hospital Zhengzhou, He'nan Province, China
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Tang L, Li P, Jang M, Zhu W. Circular RNAs and Cardiovascular Regeneration. Front Cardiovasc Med 2021; 8:672600. [PMID: 33928139 PMCID: PMC8076501 DOI: 10.3389/fcvm.2021.672600] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 03/22/2021] [Indexed: 01/22/2023] Open
Abstract
circular RNAs (circRNAs) are a type of non-coding RNAs that are widely present in eukaryotic cells. They have the characteristics of stable structure, high abundance, and cell or tissue specific expression. circRNAs are single-stranded RNAs that are covalently back spliced to form closed circular loops. They may participate in gene expression and regulation through a variety of action modes. circRNAs can encode proteins or function by acting as miRNA sponges for protein translation. Since 2016, a growing number of research studies have shown that circRNAs play important role in the pathogenesis of cardiovascular disease. With the construction of circRNA database, the differential expression of circRNAs in the heart tissue samples from different species and the gradual elucidation of its mode of action in disease may become an ideal diagnosis biomarker and an effective therapeutic target. What can be expected surely has a broader application prospect. In this review, we summarize recent publications on circRNA biogenesis, expression profiles, functions, and the most recent studies of circRNAs in the field of cardiovascular diseases with special emphasis on cardiac regeneration.
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Affiliation(s)
- Ling Tang
- Department of Cardiovascular Diseases, Physiology and Biomedical Engineering, Center of Regenerative Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Pengsheng Li
- Department of Cardiovascular Diseases, Physiology and Biomedical Engineering, Center of Regenerative Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Michelle Jang
- Department of Cardiovascular Diseases, Physiology and Biomedical Engineering, Center of Regenerative Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Wuqiang Zhu
- Department of Cardiovascular Diseases, Physiology and Biomedical Engineering, Center of Regenerative Medicine, Mayo Clinic, Scottsdale, AZ, United States
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Zhao C, Liu J, Ge W, Li Z, Lv M, Feng Y, Liu X, Liu B, Zhang Y. Identification of Regulatory circRNAs Involved in the Pathogenesis of Acute Myocardial Infarction. Front Genet 2021; 11:626492. [PMID: 33613625 PMCID: PMC7886988 DOI: 10.3389/fgene.2020.626492] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 12/24/2020] [Indexed: 12/12/2022] Open
Abstract
Background Acute myocardial infarction (AMI) has high morbidity and mortality worldwide. However, the pathogenesis of AMI is still unclear, and the impact of circular RNAs (circRNAs) on AMI has rarely been recognized and needs to be explored. Materials and Methods The circRNA array was applied to investigate the expression level of circRNAs in the blood samples of coronary arteries of three AMI patients and three normal persons. Principal component analysis (PCA) and unsupervised clustering analysis were performed to reveal the distinguished expression patterns of circRNAs. The miRNA expression profiles of AMI patients were identified from a public dataset from the Gene Expression Omnibus (GEO) database (GSE31568). The miRNA binding sites on the circRNAs were predicted by miRanda. The miRNA enrichment analysis and annotation tool were used to explore the pathways that the dysregulated circRNAs may participate in. Results In total, 142 differentially expressed circRNAs, including 89 upregulated and 53 downregulated in AMI samples, were identified by the differential expression analysis. AMI patients had quite different circRNA expression profiles to those of normal controls. Functional characterization revealed that circRNAs that had the potential to regulate miRNAs were mainly involved in seven pathways, such as the Runt-related transcription factor-1 (RUNX1) expression and activity-related pathway. Specifically, hsa_circRNA_001654, hsa_circRNA_091761, hsa_circRNA_405624, and hsa_circRNA_406698 were predicted to sponge four miRNAs including hsa-miR-491-3p, hsa-miR-646, hsa-miR-603, and hsa-miR-922, thereby regulating RUNX1 expression or activity. Conclusion We identified dysregulated blood circRNAs in the coronary arteries of AMI patients and predicted that four upregulated circRNAs were involved in the regulation of RUNX1 expression or activity through sponging four miRNAs.
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Affiliation(s)
- Cuimei Zhao
- Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jingjing Liu
- Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Wen Ge
- Department of Cardiothoracic Surgery, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai, China
| | - Zhi Li
- Department of Cardiovascular Surgery, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mengwei Lv
- Shanghai East Hospital of Clinical Medical College, Nanjing Medical University, Shanghai, China.,Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yipeng Feng
- The First Clinical Medical College, Nanjing Medical University, Nanjing, China
| | - Xuebo Liu
- Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ban Liu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yangyang Zhang
- Shanghai East Hospital of Clinical Medical College, Nanjing Medical University, Shanghai, China.,Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Erratum to "Expression Profiles and Ontology Analysis of Circular RNAs in a Mouse Model of Myocardial Ischemia/Reperfusion Injury". BIOMED RESEARCH INTERNATIONAL 2020; 2020:2097954. [PMID: 33354563 PMCID: PMC7735835 DOI: 10.1155/2020/2097954] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 11/18/2020] [Indexed: 11/18/2022]
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