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Role of Circular RNAs in the Pathogenesis of Cardiovascular Disease

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Abstract

Circular RNAs (circRNAs) are single-strand covalently closed circular noncoding RNAs that are endogenous transcripts generated from linear precursor mRNA through a backsplicing mechanism. With the development of high-throughput sequencing technology, a number of circRNAs have been identified and proved to play key roles in various pathophysiological processes, such as metabolic diseases, cancers, and cardiovascular diseases. An increasing number of studies have shown that circRNAs are widely expressed in cardiac tissues and play important roles in the development of multiple cardiovascular diseases. Here, we review the current understanding of circRNA biogenesis and functions and the roles of circRNAs in cardiovascular diseases. We also highlight the molecular mechanisms underlying the role of circRNAs in the pathogenesis of cardiovascular diseases. A better understanding of the biological function of circRNAs in cardiovascular diseases will be helpful for the development of effective biomarkers for the diagnosis and treatment of these diseases.

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References

  1. Han, B., Chao, J., & Yao, H. (2018). Circular RNA and its mechanisms in disease: From the bench to the clinic. Pharmacology & Therapeutics, 187, 31–44. https://doi.org/10.1016/j.pharmthera.2018.01.010.

    Article  CAS  Google Scholar 

  2. Fischer, J. W., & Leung, A. K. (2017). CircRNAs: a regulator of cellular stress. Critical Reviews in Biochemistry and Molecular Biology, 52(2), 220–233. https://doi.org/10.1080/10409238.2016.1276882.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Jeck, W. R., & Sharpless, N. E. (2014). Detecting and characterizing circular RNAs. Nature Biotechnology, 32(5), 453–461. https://doi.org/10.1038/nbt.2890.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Abdelmohsen, K., Panda, A. C., Munk, R., Grammatikakis, I., Dudekula, D. B., De, S., et al. (2017). Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1. RNA Biology, 14(3), 361–369. https://doi.org/10.1080/15476286.2017.1279788.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Ashwal-Fluss, R., Meyer, M., Pamudurti, N. R., Ivanov, A., Bartok, O., Hanan, M., et al. (2014). circRNA biogenesis competes with pre-mRNA splicing. Molecular Cell, 56(1), 55–66. https://doi.org/10.1016/j.molcel.2014.08.019.

    Article  CAS  PubMed  Google Scholar 

  6. Shan, K., Liu, C., Liu, B. H., Chen, X., Dong, R., Liu, X., et al. (2017). Circular noncoding RNA HIPK3 mediates retinal vascular dysfunction in diabetes mellitus. Circulation, 136(17), 1629–1642. https://doi.org/10.1161/circulationaha.117.029004.

    Article  CAS  PubMed  Google Scholar 

  7. Boeckel, J. N., Jae, N., Heumuller, A. W., Chen, W., Boon, R. A., Stellos, K., et al. (2015). Identification and characterization of hypoxia-regulated endothelial circular RNA. Circulation Research, 117(10), 884–890. https://doi.org/10.1161/circresaha.115.306319.

    Article  CAS  PubMed  Google Scholar 

  8. Du, W. W., Yang, W., Liu, E., Yang, Z., Dhaliwal, P., & Yang, B. B. (2016). Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Research, 44(6), 2846–2858. https://doi.org/10.1093/nar/gkw027.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Jordan, M. C., Henderson, S. A., Han, T., Fishbein, M. C., Philipson, K. D., & Roos, K. P. (2010). Myocardial function with reduced expression of the sodium-calcium exchanger. Journal of Cardiac Failure, 16(9), 786–796. https://doi.org/10.1016/j.cardfail.2010.03.012.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Fang, Y., Wang, X., Li, W., Han, J., **, J., Su, F., et al. (2018). Screening of circular RNAs and validation of circANKRD36 associated with inflammation in patients with type 2 diabetes mellitus. International Journal of Molecular Medicine, 42(4), 1865–1874. https://doi.org/10.3892/ijmm.2018.3783.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Klinge, C. (2018). Non-coding RNAs in breast cancer: intracellular and intercellular communication. Non-Coding RNA, 4(4), 40. https://doi.org/10.3390/ncrna4040040.

    Article  CAS  PubMed Central  Google Scholar 

  12. Shang, Q., Yang, Z., Jia, R., & Ge, S. (2019). The novel roles of circRNAs in human cancer. Molecular Cancer, 18(1), 6. https://doi.org/10.1186/s12943-018-0934-6.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Wang, K., Long, B., Liu, F., Wang, J. X., Liu, C. Y., Zhao, B., et al. (2016). A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. European Heart Journal, 37(33), 2602–2611. https://doi.org/10.1093/eurheartj/ehv713.

    Article  CAS  PubMed  Google Scholar 

  14. Townsend, N., Nichols, M., Scarborough, P., & Rayner, M. (2015). Cardiovascular disease in Europe--epidemiological update 2015. European Heart Journal, 36(40), 2696–2705. https://doi.org/10.1093/eurheartj/ehv428.

    Article  PubMed  Google Scholar 

  15. Townsend, N., Wilson, L., Bhatnagar, P., Wickramasinghe, K., Rayner, M., & Nichols, M. (2016). Cardiovascular disease in Europe: epidemiological update 2016. European Heart Journal, 37(42), 3232–3245. https://doi.org/10.1093/eurheartj/ehw334.

    Article  PubMed  Google Scholar 

  16. Li, M., Ding, W., Sun, T., Tariq, M. A., Xu, T., Li, P., et al. (2018). Biogenesis of circular RNAs and their roles in cardiovascular development and pathology. The FEBS Journal, 285(2), 220–232. https://doi.org/10.1111/febs.14191.

    Article  CAS  PubMed  Google Scholar 

  17. Wang, H., Yang, J., Yang, J., Fan, Z., & Yang, C. (2016). Circular RNAs: novel rising stars in cardiovascular disease research. International Journal of Cardiology, 202, 726–727. https://doi.org/10.1016/j.ijcard.2015.10.051.

    Article  PubMed  Google Scholar 

  18. Devaux, Y., Creemers, E. E., Boon, R. A., Werfel, S., Thum, T., Engelhardt, S., et al. (2017). Circular RNAs in heart failure. European Journal of Heart Failure, 19(6), 701–709. https://doi.org/10.1002/ejhf.801.

    Article  CAS  PubMed  Google Scholar 

  19. Fan, X., Weng, X., Zhao, Y., Chen, W., Gan, T., & Xu, D. (2017). Circular RNAs in cardiovascular disease: an overview. BioMed Research International, 2017, 5135781. https://doi.org/10.1155/2017/5135781.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Memczak, S., Papavasileiou, P., Peters, O., & Rajewsky, N. (2015). Identification and characterization of circular RNAs as a new class of putative biomarkers in human blood. PLoS One, 10(10), e0141214. https://doi.org/10.1371/journal.pone.0141214.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Greene, J., Baird, A. M., Brady, L., Lim, M., Gray, S. G., McDermott, R., et al. (2017). Circular RNAs: biogenesis, function and role in human diseases. Frontiers in Molecular Biosciences, 4, 38. https://doi.org/10.3389/fmolb.2017.00038.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Sanger, H. L., Klotz, G., Riesner, D., Gross, H. J., & Kleinschmidt, A. K. (1976). Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proceedings of the National Academy of Sciences of the United States of America, 73(11), 3852–3856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hsu, M. T., & Coca-Prados, M. (1979). Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells. Nature, 280(5720), 339–340.

    Article  CAS  PubMed  Google Scholar 

  24. Cocquerelle, C., Daubersies, P., Majerus, M. A., Kerckaert, J. P., & Bailleul, B. (1992). Splicing with inverted order of exons occurs proximal to large introns. The EMBO Journal, 11(3), 1095–1098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nigro, J. M., Cho, K. R., Fearon, E. R., Kern, S. E., Ruppert, J. M., Oliner, J. D., et al. (1991). Scrambled exons. Cell, 64(3), 607–613. https://doi.org/10.1016/0092-8674(91)90244-S.

    Article  CAS  PubMed  Google Scholar 

  26. Pasman, Z., Been, M. D., & Garcia-Blanco, M. A. (1996). Exon circularization in mammalian nuclear extracts. RNA, 2(6), 603–610.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Capel, B., Swain, A., Nicolis, S., Hacker, A., Walter, M., Koopman, P., et al. (1993). Circular transcripts of the testis-determining gene Sry in adult mouse testis. Cell, 73(5), 1019–1030. https://doi.org/10.1016/0092-8674(93)90279-Y.

    Article  CAS  PubMed  Google Scholar 

  28. Surono, A., Takeshima, Y., Wibawa, T., Ikezawa, M., Nonaka, I., & Matsuo, M. (1999). Circular dystrophin RNAs consisting of exons that were skipped by alternative splicing. Human Molecular Genetics, 8(3), 493–500.

    Article  CAS  PubMed  Google Scholar 

  29. Li, X. F., & Lytton, J. (1999). A circularized sodium-calcium exchanger exon 2 transcript. The Journal of Biological Chemistry, 274(12), 8153–8160. https://doi.org/10.1074/jbc.274.12.8153.

    Article  CAS  PubMed  Google Scholar 

  30. Houseley, J. M., Garcia-Casado, Z., Pascual, M., Paricio, N., O’Dell, K. M., Monckton, D. G., et al. (2006). Noncanonical RNAs from transcripts of the Drosophila muscleblind gene. The Journal of Heredity, 97(3), 253–260. https://doi.org/10.1093/jhered/esj037.

    Article  CAS  PubMed  Google Scholar 

  31. Cocquerelle, C., Mascrez, B., Hetuin, D., & Bailleul, B. (1993). Mis-splicing yields circular RNA molecules. The FASEB Journal, 7(1), 155–160.

    Article  CAS  PubMed  Google Scholar 

  32. Salzman, J., Gawad, C., Wang, P. L., Lacayo, N., & Brown, P. O. (2012). Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One, 7(2), e30733. https://doi.org/10.1371/journal.pone.0030733.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Salzman, J., Chen, R. E., Olsen, M. N., Wang, P. L., & Brown, P. O. (2013). Cell-type specific features of circular RNA expression. PLoS Genetics, 9(9), e1003777. https://doi.org/10.1371/journal.pgen.1003777.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K., Burd, C. E., Liu, J., et al. (2013). Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA, 19(2), 141–157. https://doi.org/10.1261/rna.035667.112.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., et al. (2013). Circular RNAs are a large class of animal RNAs with regulatory potency. Nature, 495(7441), 333–338. https://doi.org/10.1038/nature11928.

    Article  CAS  PubMed  Google Scholar 

  36. Guo, J. U., Agarwal, V., Guo, H., & Bartel, D. P. (2014). Expanded identification and characterization of mammalian circular RNAs. Genome Biology, 15(7), 409. https://doi.org/10.1186/s13059-014-0409-z.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Wang, Y., & Wang, Z. (2015). Efficient backsplicing produces translatable circular mRNAs. RNA, 21(2), 172–179. https://doi.org/10.1261/rna.048272.114.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Westholm, J. O., Miura, P., Olson, S., Shenker, S., Joseph, B., Sanfilippo, P., et al. (2014). Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. Cell Reports, 9(5), 1966–1980. https://doi.org/10.1016/j.celrep.2014.10.062.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang, X. O., Wang, H. B., Zhang, Y., Lu, X., Chen, L. L., & Yang, L. (2014). Complementary sequence-mediated exon circularization. Cell, 159(1), 134–147. https://doi.org/10.1016/j.cell.2014.09.001.

    Article  CAS  PubMed  Google Scholar 

  40. Veno, M. T., Hansen, T. B., Veno, S. T., Clausen, B. H., Grebing, M., Finsen, B., et al. (2015). Spatio-temporal regulation of circular RNA expression during porcine embryonic brain development. Genome Biology, 16, 245. https://doi.org/10.1186/s13059-015-0801-3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K., et al. (2013). Natural RNA circles function as efficient microRNA sponges. Nature, 495(7441), 384–388. https://doi.org/10.1038/nature11993.

    Article  CAS  PubMed  Google Scholar 

  42. Pamudurti, N. R., Bartok, O., Jens, M., Ashwal-Fluss, R., Stottmeister, C., Ruhe, L., et al. (2017). Translation of CircRNAs. Mol Cell, 66(1), 9–21.e27. https://doi.org/10.1016/j.molcel.2017.02.021.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Burset, M., Seledtsov, I. A., & Solovyev, V. V. (2000). Analysis of canonical and non-canonical splice sites in mammalian genomes. Nucleic Acids Research, 28(21), 4364–4375. https://doi.org/10.1093/nar/28.21.4364.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Altesha, M. A., Ni, T., Khan, A., Liu, K., & Zheng, X. (2019). Circular RNA in cardiovascular disease. Journal of Cellular Physiology, 234(5), 5588–5600. https://doi.org/10.1002/jcp.27384.

    Article  CAS  PubMed  Google Scholar 

  45. Li, X., Yang, L., & Chen, L. L. (2018). The biogenesis, functions, and challenges of circular RNAs. Molecular Cell, 71(3), 428–442. https://doi.org/10.1016/j.molcel.2018.06.034.

    Article  CAS  PubMed  Google Scholar 

  46. Chen, L. L., & Yang, L. (2015). Regulation of circRNA biogenesis. RNA Biology, 12(4), 381–388. https://doi.org/10.1080/15476286.2015.1020271.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Chen, W., & Schuman, E. (2016). Circular RNAs in brain and other tissues: a functional enigma. Trends in Neurosciences, 39(9), 597–604. https://doi.org/10.1016/j.tins.2016.06.006.

    Article  CAS  PubMed  Google Scholar 

  48. Ebbesen, K. K., Kjems, J., & Hansen, T. B. (2016). Circular RNAs: identification, biogenesis and function. Biochimica et Biophysica Acta, 1859(1), 163–168. https://doi.org/10.1016/j.bbagrm.2015.07.007.

    Article  CAS  PubMed  Google Scholar 

  49. Li, Z., Huang, C., Bao, C., Chen, L., Lin, M., Wang, X., et al. (2015). Exon-intron circular RNAs regulate transcription in the nucleus. Nature Structural & Molecular Biology, 22(3), 256–264. https://doi.org/10.1038/nsmb.2959.

    Article  CAS  Google Scholar 

  50. Zhang, Y., Zhang, X. O., Chen, T., **ang, J. F., Yin, Q. F., **ng, Y. H., et al. (2013). Circular intronic long noncoding RNAs. Molecular Cell, 51(6), 792–806. https://doi.org/10.1016/j.molcel.2013.08.017.

    Article  CAS  PubMed  Google Scholar 

  51. Salmena, L., Poliseno, L., Tay, Y., Kats, L., & Pandolfi, P. P. (2011). A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell, 146(3), 353–358. https://doi.org/10.1016/j.cell.2011.07.014.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Piwecka, M., Glazar, P., Hernandez-Miranda, L. R., Memczak, S., Wolf, S. A., Rybak-Wolf, A., et al. (2017). Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science, 357(6357), eaam8526. https://doi.org/10.1126/science.aam8526.

    Article  CAS  PubMed  Google Scholar 

  53. Holdt, L. M., Stahringer, A., Sass, K., Pichler, G., Kulak, N. A., Wilfert, W., et al. (2016). Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nature Communications, 7, 12429. https://doi.org/10.1038/ncomms12429.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Chen, C. Y., & Sarnow, P. (1995). Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science, 268(5209), 415–417.

    Article  CAS  PubMed  Google Scholar 

  55. Legnini, I., Di Timoteo, G., Rossi, F., Morlando, M., Briganti, F., Sthandier, O., et al. (2017). Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol Cell, 66(1), 22–37.e29. https://doi.org/10.1016/j.molcel.2017.02.017.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Yang, Y., Fan, X., Mao, M., Song, X., Wu, P., Zhang, Y., et al. (2017). Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Research, 27(5), 626–641. https://doi.org/10.1038/cr.2017.31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Conn, V. M., Hugouvieux, V., Nayak, A., Conos, S. A., Capovilla, G., Cildir, G., et al. (2017). A circRNA from SEPALLATA3 regulates splicing of its cognate mRNA through R-loop formation. [Letter]. Nat Plants, 3, 17053. https://doi.org/10.1038/nplants.2017.53.

    Article  CAS  PubMed  Google Scholar 

  58. Werfel, S., Nothjunge, S., Schwarzmayr, T., Strom, T. M., Meitinger, T., & Engelhardt, S. (2016). Characterization of circular RNAs in human, mouse and rat hearts. Journal of Molecular and Cellular Cardiology, 98, 103–107. https://doi.org/10.1016/j.yjmcc.2016.07.007.

    Article  CAS  PubMed  Google Scholar 

  59. Jakobi, T., Czaja-Hasse, L. F., Reinhardt, R., & Dieterich, C. (2016). Profiling and validation of the circular RNA repertoire in adult murine hearts. Genomics, Proteomics & Bioinformatics, 14(4), 216–223. https://doi.org/10.1016/j.gpb.2016.02.003.

    Article  Google Scholar 

  60. Tan, W. L., Lim, B. T., Anene-Nzelu, C. G., Ackers-Johnson, M., Dashi, A., See, K., et al. (2017). A landscape of circular RNA expression in the human heart. Cardiovascular Research, 113(3), 298–309. https://doi.org/10.1093/cvr/cvw250.

    Article  CAS  PubMed  Google Scholar 

  61. Broadbent, H. M., Peden, J. F., Lorkowski, S., Goel, A., Ongen, H., Green, F., et al. (2008). Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Human Molecular Genetics, 17(6), 806–814. https://doi.org/10.1093/hmg/ddm352.

    Article  CAS  PubMed  Google Scholar 

  62. Hall Ignacio, F., Climent, M., Quintavalle, M., Farina Floriana, M., Schorn, T., Zani, S., et al. (2019). Circ_Lrp6, a circular RNA enriched in vascular smooth muscle cells, acts as a sponge regulating miRNA-145 function. Circulation Research, 124(4), 498–510. https://doi.org/10.1161/CIRCRESAHA.118.314240.

    Article  CAS  PubMed  Google Scholar 

  63. Yang, L., Yang, F., Zhao, H., Wang, M., & Zhang, Y. (2019). Circular RNA circCHFR facilitates the proliferation and migration of vascular smooth muscle via miR-370/FOXO1/cyclin D1 pathway. Molecular Therapy--Nucleic Acids, 16, 434–441. https://doi.org/10.1016/j.omtn.2019.02.028.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Geng, H.-H., Li, R., Su, Y.-M., **ao, J., Pan, M., Cai, X.-X., et al. (2016). The circular RNA Cdr1as promotes myocardial infarction by mediating the regulation of miR-7a on its target genes expression. PLoS One, 11(3), e0151753–e0151753. https://doi.org/10.1371/journal.pone.0151753.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Deng, Y.-Y., Zhang, W., She, J., Zhang, L., Chen, T., Zhou, J., et al. (2016). GW27-e1167 circular RNA related to PPARγ function as ceRNA of microRNA in human acute myocardial infarction. Journal of the American College of Cardiology, 68(16, Supplement), C51–C52. https://doi.org/10.1016/j.jacc.2016.07.189.

    Article  Google Scholar 

  66. Li, M., Ding, W., Tariq, M. A., Chang, W., Zhang, X., Xu, W., et al. (2018). A circular transcript of ncx1 gene mediates ischemic myocardial injury by targeting miR-133a-3p. Theranostics, 8(21), 5855–5869. https://doi.org/10.7150/thno.27285.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Wang, K., Gan, T. Y., Li, N., Liu, C. Y., Zhou, L. Y., Gao, J. N., et al. (2017). Circular RNA mediates cardiomyocyte death via miRNA-dependent upregulation of MTP18 expression. Cell Death and Differentiation, 24(6), 1111–1120. https://doi.org/10.1038/cdd.2017.61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Huang, S., Li, X., Zheng, H., Si, X., Li, B., Wei, G., et al. (2019). Loss of super-enhancer-regulated circRNA Nfix induces cardiac regeneration after myocardial infarction in adult mice. Circulation, 139(25), 2857–2876. https://doi.org/10.1161/circulationaha.118.038361.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Zhou, L. Y., Zhai, M., Huang, Y., Xu, S., An, T., Wang, Y. H., et al. (2019). The circular RNA ACR attenuates myocardial ischemia/reperfusion injury by suppressing autophagy via modulation of the Pink1/ FAM65B pathway. Cell Death and Differentiation, 26(7), 1299–1315. https://doi.org/10.1038/s41418-018-0206-4.

    Article  CAS  PubMed  Google Scholar 

  70. Tang, C. M., Zhang, M., Huang, L., Hu, Z. Q., Zhu, J. N., **ao, Z., et al. (2017). CircRNA_000203 enhances the expression of fibrosis-associated genes by derepressing targets of miR-26b-5p, Col1a2 and CTGF, in cardiac fibroblasts. Scientific Reports, 7, 40342. https://doi.org/10.1038/srep40342.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Zhou, B., & Yu, J. W. (2017). A novel identified circular RNA, circRNA_010567, promotes myocardial fibrosis via suppressing miR-141 by targeting TGF-beta1. Biochemical and Biophysical Research Communications, 487(4), 769–775. https://doi.org/10.1016/j.bbrc.2017.04.044.

    Article  CAS  PubMed  Google Scholar 

  72. Zhu, Y., Pan, W., Yang, T., Meng, X., Jiang, Z., Tao, L., et al. (2019). Upregulation of circular RNA CircNFIB attenuates cardiac fibrosis by sponging miR-433. Frontiers in Genetics, 10, 564. https://doi.org/10.3389/fgene.2019.00564.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Khan Mohsin, A. F., Reckman Yolan, J., Aufiero, S., van den Hoogenhof Maarten, M. G., van der Made, I., Beqqali, A., et al. (2016). RBM20 regulates circular RNA production from the titin gene. Circulation Research, 119(9), 996–1003. https://doi.org/10.1161/CIRCRESAHA.116.309568.

    Article  CAS  PubMed  Google Scholar 

  74. Lim, T. B., Aliwarga, E., Luu, T. D. A., Li, Y. P., Ng, S. L., Annadoray, L., et al. (2019). Targeting the highly abundant circular RNA circSlc8a1 in cardiomyocytes attenuates pressure overload induced hypertrophy. Cardiovascular Research. https://doi.org/10.1093/cvr/cvz130.

  75. Du, W. W., Yang, W., Chen, Y., Wu, Z. K., Foster, F. S., Yang, Z., et al. (2017). Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses. European Heart Journal, 38(18), 1402–1412. https://doi.org/10.1093/eurheartj/ehw001.

    Article  CAS  PubMed  Google Scholar 

  76. Vausort, M., Salgado-Somoza, A., Zhang, L., Leszek, P., Scholz, M., Teren, A., et al. (2016). Myocardial infarction-associated circular RNA predicting left ventricular dysfunction. Journal of the American College of Cardiology, 68(11), 1247–1248. https://doi.org/10.1016/j.jacc.2016.06.040.

    Article  PubMed  Google Scholar 

  77. Bazan, H. A., Hatfield, S. A., Brug, A., Brooks, A. J., Lightell, D. J., Jr., & Woods, T. C. (2017). Carotid plaque rupture is accompanied by an increase in the ratio of serum circR-284 to miR-221 levels. Circulation. Cardiovascular Genetics, 10(4), e001720. https://doi.org/10.1161/circgenetics.117.001720.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Wang, L., Shen, C., Wang, Y., Zou, T., Zhu, H., Lu, X., et al. (2019). Identification of circular RNA Hsa_circ_0001879 and Hsa_circ_0004104 as novel biomarkers for coronary artery disease. Atherosclerosis, 286, 88–96. https://doi.org/10.1016/j.atherosclerosis.2019.05.006.

    Article  CAS  PubMed  Google Scholar 

  79. (2016). Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet, 388(10053), 1459–1544. https://doi.org/10.1016/s0140-6736(16)31012-1.

  80. Biros, E., Cooper, M., Palmer, L. J., Walker, P. J., Norman, P. E., & Golledge, J. (2010). Association of an allele on chromosome 9 and abdominal aortic aneurysm. Atherosclerosis, 212(2), 539–542. https://doi.org/10.1016/j.atherosclerosis.2010.06.015.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Bown, M. J., Braund, P. S., Thompson, J., London, N. J., Samani, N. J., & Sayers, R. D. (2008). Association between the coronary artery disease risk locus on chromosome 9p21.3 and abdominal aortic aneurysm. Circulation. Cardiovascular Genetics, 1(1), 39–42. https://doi.org/10.1161/circgenetics.108.789727.

    Article  PubMed  Google Scholar 

  82. Ye, S., Willeit, J., Kronenberg, F., Xu, Q., & Kiechl, S. (2008). Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study. Journal of the American College of Cardiology, 52(5), 378–384. https://doi.org/10.1016/j.jacc.2007.11.087.

    Article  CAS  PubMed  Google Scholar 

  83. Dietrich, N., Bracken, A. P., Trinh, E., Schjerling, C. K., Koseki, H., Rappsilber, J., et al. (2007). Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus. The EMBO Journal, 26(6), 1637–1648. https://doi.org/10.1038/sj.emboj.7601632.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A., & van Lohuizen, M. (1999). The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature, 397(6715), 164–168. https://doi.org/10.1038/16476.

    Article  CAS  PubMed  Google Scholar 

  85. Swynghedauw, B. (1999). Molecular mechanisms of myocardial remodeling. Physiological Reviews, 79(1), 215–262. https://doi.org/10.1152/physrev.1999.79.1.215.

    Article  CAS  PubMed  Google Scholar 

  86. Zheng, Q., Bao, C., Guo, W., Li, S., Chen, J., Chen, B., et al. (2016). Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nature Communications, 7, 11215. https://doi.org/10.1038/ncomms11215.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Dong, Y., Liu, C., Zhao, Y., Ponnusamy, M., Li, P., & Wang, K. (2018). Role of noncoding RNAs in regulation of cardiac cell death and cardiovascular diseases. Cellular and Molecular Life Sciences, 75(2), 291–300. https://doi.org/10.1007/s00018-017-2640-8.

    Article  CAS  PubMed  Google Scholar 

  88. Bayoumi, A. S., Aonuma, T., Teoh, J. P., Tang, Y. L., & Kim, I. M. (2018). Circular noncoding RNAs as potential therapies and circulating biomarkers for cardiovascular diseases. Acta Pharmacologica Sinica, 39(7), 1100–1109. https://doi.org/10.1038/aps.2017.196.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Wu, H. J., Zhang, C. Y., Zhang, S., Chang, M., & Wang, H. Y. (2016). Microarray expression profile of circular RNAs in heart tissue of mice with myocardial infarction-induced heart failure. Cellular Physiology and Biochemistry, 39(1), 205–216. https://doi.org/10.1159/000445617.

    Article  CAS  PubMed  Google Scholar 

  90. Heumüller Andreas, W., & Dimmeler, S. (2019). Circular RNA control of vascular smooth muscle cell functions. Circulation Research, 124(4), 456–458. https://doi.org/10.1161/CIRCRESAHA.118.314521.

    Article  CAS  PubMed  Google Scholar 

  91. Wu, Q. Q., **ao, Y., Yuan, Y., Ma, Z. G., Liao, H. H., Liu, C., et al. (2017). Mechanisms contributing to cardiac remodelling. Clinical Science (London, England), 131(18), 2319–2345. https://doi.org/10.1042/cs20171167.

    Article  CAS  Google Scholar 

  92. Steinberg, B. A., Mulpuru, S. K., Fang, J. C., & Gersh, B. J. (2017). Sudden death mechanisms in nonischemic cardiomyopathies: Insights gleaned from clinical implantable cardioverter-defibrillator trials. Heart Rhythm, 14(12), 1839–1848. https://doi.org/10.1016/j.hrthm.2017.09.025.

    Article  PubMed  Google Scholar 

  93. Kimura, W., ** identifies cycling cardiomyocytes in the adult heart. Nature, 523(7559), 226–230. https://doi.org/10.1038/nature14582.

    Article  CAS  PubMed  Google Scholar 

  94. Gupta, S. K., Garg, A., Bar, C., Chatterjee, S., Foinquinos, A., Milting, H., et al. (2018). Quaking inhibits doxorubicin-mediated cardiotoxicity through regulation of cardiac circular RNA expression. Circulation Research, 122(2), 246–254. https://doi.org/10.1161/circresaha.117.311335.

    Article  CAS  PubMed  Google Scholar 

  95. Koh, W., Pan, W., Gawad, C., Fan, H. C., Kerchner, G. A., Wyss-Coray, T., et al. (2014). Noninvasive in vivo monitoring of tissue-specific global gene expression in humans. Proceedings of the National Academy of Sciences of the United States of America, 111(20), 7361–7366. https://doi.org/10.1073/pnas.1405528111.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Zhao, Z., Li, X., Gao, C., Jian, D., Hao, P., Rao, L., et al. (2017). Peripheral blood circular RNA hsa_circ_0124644 can be used as a diagnostic biomarker of coronary artery disease. Scientific Reports, 7, 39918. https://doi.org/10.1038/srep39918.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Funding

This work was funded by the National Natural Science Foundation of China (81741173, 31430041).

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  1. Baowei Li and Yuzhen Li contributed equally to this work.

Authors and Affiliations

  1. Institute for Translational Medicine, Qingdao University, Qingdao, 266021, China

    Baowei Li, Ying Liu, Qihui Zhou, Man Wang & Peifeng Li

  2. Department of Pathophysiology, Institute of Basic Medical Science, PLA General Hospital, Bei**g, 100853, China

    Yuzhen Li

  3. Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266021, China

    Longgang Hu & Yi An

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  1. Baowei Li
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Li, B., Li, Y., Hu, L. et al. Role of Circular RNAs in the Pathogenesis of Cardiovascular Disease. J. of Cardiovasc. Trans. Res. 13, 572–583 (2020). https://doi.org/10.1007/s12265-019-09912-2

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