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N6-Adenosine Methylation (m6A) RNA Modification: an Emerging Role in Cardiovascular Diseases

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Abstract

N6-methyladenosine (m6A) is the most abundant and prevalent epigenetic modification of mRNA in mammals. This dynamic modification is regulated by m6A methyltransferases and demethylases, which control the fate of target mRNAs through influencing splicing, translation and decay. Recent studies suggest that m6A modification plays an important role in the progress of cardiac remodeling and cardiomyocyte contractile function. However, the exact roles of m6A in cardiovascular diseases (CVDs) have not been fully explained. In this review, we summarize the current roles of the m6A methylation in the progress of CVDs, such as cardiac remodeling, heart failure, atherosclerosis (AS), and congenital heart disease. Furthermore, we seek to explore the potential risk mechanisms of m6A in CVDs, including obesity, inflammation, adipogenesis, insulin resistance (IR), hypertension, and type 2 diabetes mellitus (T2DM), which may provide novel therapeutic targets for the treatment of CVDs.

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Abbreviations

m6A:

N6-methyladenosine

AS:

Atherosclerosis

IR:

Insulin resistance

T2DM:

Type 2 diabetes mellitus

WTAP:

Wilms’ tumor 1-associating protein

RBM15:

RNA-binding motif protein 15

METTL3:

Methyltransferase-like 3

METTL14:

Methyltransferase-like 14

ALKBH5:

ALKB homolog 5

FTO:

Fat mass and obesity-associated

YTH:

YT521-B homology

CVDs:

Cardiovascular diseases

HF:

Heart failure

ESC:

Embryonic stem cell

ZC3H13:

Zinc finger CCCH domain-containing protein 13

RBM:

RNA-binding motif protein

H3K36me3:

Histone H3 lysine 36 trimethylation

ZCCHC4:

Zinc finger CCHC-type-containing 4

m6Am:

N6, 2’-O-dimethyladenosine

eIF3:

Eukaryotic initiation factor 3

HfpEF:

HF with preserved ejection fraction

HfrEF:

HF with reduced ejection fraction

HDPCs:

Human dental pulp cells

BMI:

Body mass index

SNPs:

Single nucleotide polymorphisins

TTP:

The RBP tristetraprolin

MEC:

Mitotic clonal expansion

CCNA2:

Cyclin A2

CDK2:

Cyclin-dependent kinase 2

PNPLA2:

Patatin-like phospholipase domain containing 2

MTCH2:

Mitochondrial carrier homology 2

EGCG:

Epigallocatechin gallate

Zfp217:

Zinc finger protein 217

HOMA:

Homeostasis Model Assessment

BP:

Blood pressure

G6Pc:

Glucose-6-phosphatase catalytic subunit

FOXO1:

Forkhead box O1

6mA:

N6-methyladenine DNA

5mC:

5-methylcytosine

N6AMT1:

N-6 adenine-specific DNA methyltransferase 1

meQTL:

Methylation quantitative trait loci

References

  1. Kim, T. K., Gore, S. D., & Zeidan, A. M. (2015). Epigenetic therapy in acute myeloid leukemia: current and future directions. Seminars in Hematology, 52, 172–183.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Wu, X., Sang, L., & Gong, Y. (2018). N6-methyladenine RNA modification and cancers. American Journal of Cancer Research, 8, 1957–1966.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Roundtree, I. A., Evans, M. E., Pan, T., & He, C. (2017). Dynamic RNA modifications in gene expression regulation. Cell, 169, 1187–1200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Adams, J. M., & Cory, S. (1975). Modified nucleosides and bizarre 5’-termini in mouse myeloma mRNA. Nature, 255, 28–33.

    Article  CAS  PubMed  Google Scholar 

  5. Desrosiers, R., Friderici, K., & Rottman, F. (1974). Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proceedings of the National Academy of Sciences of the United States of America, 71, 3971–3975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yang, D., Qiao, J., Wang, G., Lan, Y., Li, G., Guo, X., et al. (2018). N6-Methyladenosine modification of lincRNA 1281 is critically required for mESC differentiation potential. Nucleic Acids Research, 46(8), 3906–3920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alarcón, C. R., Lee, H., Goodarzi, H., Halberg, N., & Tavazoie, S. F. (2015). N6-methyladenosine marks primary microRNAs for processing. Nature, 519(7544), 482–485.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Chen, Y. G., Chen, R., Ahmad, S., Verma, R., Kasturi, S. P., Amaya, L., et al. (2019). N6-methyladenosine modification controls circular rna immunity. Molecular Cell, 76(1), 96–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jia, G., Fu, Y., & He, C. (2013). Reversible RNA adenosine methylation in biological regulation. Trends in Genetics, 29, 108–115.

    Article  CAS  PubMed  Google Scholar 

  10. Niu, Y., Zhao, X., Wu, Y. S., & Li, M. M. (2013). N6-methyl-adenosine (m6A) in RNA: an old modificatio with a novel epigenetic function. Genomics, Proteomics & Bioinformatics, 11, 8–17.

    Article  CAS  Google Scholar 

  11. Fustin, J. M., Doi, M., Yamaguchi, Y., & Hida, H. (2013). RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell, 155, 793–806.

    Article  CAS  PubMed  Google Scholar 

  12. Wang, X., Lu, Z., Gomez, A., & Hon, C. G. (2014). N6-methyladenosine-dependent regulation of messenger RNA stability. Nature, 505, 117–120.

    Article  PubMed  CAS  Google Scholar 

  13. Schwartz, S., Agarwala, S. D., Mumbach, M. R., & Jovanovic, M. (2013). High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell, 155, 1409–1421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dorn, L. E., Lasman, L., Chen, J., & Xu, X. (2019). The N(6)-methyladenosine mRNA methylase METTL3 controls cardiac homeostasis and hypertrophy. Circulation, 139, 533–545.

    Article  CAS  PubMed  Google Scholar 

  15. Kmietczyk, V., Riechert, E., Kalinski, L., & Boileau, E. (2019). m(6)A-mRNA methylation regulates cardiac gene expression and cellular growth. Life Science Alliance, 2, 2.

    Article  Google Scholar 

  16. Mathiyalagan, P., Adamiak, M., Mayourian, J., & Sassi, Y. (2019). FTO-dependent N(6)-methyladenosine regulates cardiac function during remodeling and repair. Circulation, 139, 518–532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Song, H., Feng, X., Zhang, H., Luo, Y., Huang, J., Lin, M., et al. (2019). METTL3 and ALKBH5 oppositely regulate m6A modification of TFEB mRNA, which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes. Autophagy, 15(8), 1419–1437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Balacco, D. L., & Soller, M. (2019). The m6A writer: rise of a machine for growing tasks. Biochemistry, 58(5), 363–378.

    Article  CAS  PubMed  Google Scholar 

  19. Frye, M., Harada, B. T., Behm, M., & He, C. (2018). RNA modifications modulate gene expression during development. Science, 361(6409), 1346–1349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Geula, S., Moshitch-Moshkovitz, S., Dominissini, D., Mansour, A. A., Kol, N., Salmon-Divon, M., et al. (2015). m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science, 347(6225), 1002–1006.

    Article  CAS  PubMed  Google Scholar 

  21. Ma, C., Chang, M., Lv, H., Zhang, Z. W., Zhang, W., He, X., et al. (2018). RNA m6A methylation participates in regulation of postnatal development of the mouse cerebellum. Genome Biology, 19(1), 68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Yoon, K. J., Ringeling, F. R., Vissers, C., Jacob, F., Pokrass, M., Jimenez-Cyrus, D., et al. (2017). Temporal control of mammalian cortical neurogenesis by m6A methylation. Cell, 171(4), 877–889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Meng, T. G., Lu, X., Guo, L., Hou, G. M., Ma, X. S., Li, Q. N., et al. (2019). Mettl14 is required for mouse postimplantation development by facilitating epiblast maturation. The FASEB Journal, 33(1), 1179–1187.

    Article  CAS  PubMed  Google Scholar 

  24. Tran, N. T., Su, H., Khodadadi-Jamayran, A., Lin, S., Zhang, L., Zhou, D., et al. (2016). The AS-RBM15 lncRNA enhances RBM15 protein translation during megakaryocyte differentiation. EMBO Reports, 17(6), 887–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Raffel, G. D., Chu, G. C., Jesneck, J. L., Cullen, D. E., Bronson, R. T., Bernard, O. A., et al. (2016). Ott1 (Rbm15) is essential for placental vascular branching morphogenesis and embryonic development of the heart and spleen. Molecular and Cellular Biology, 29(2), 333–341.

    Article  CAS  Google Scholar 

  26. Yue, Y., Liu, J., Cui, X., & Cao, J. (2018). VIRMA mediates preferential m(6)A mRNA methylation in 3’UTR and near stop codon and associates with alternative polyadenylation. Cell Discovery, 4, 10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Wen, J., Lv, R., Ma, H., & Shen, H. (2018). Zc3h13 regulates nuclear RNA m(6)A methylation and mouse embryonic stem cell self-renewal. Molecular Cell, 69, 1028–1038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Patil, D. P., Chen, C. K., & Pickering, B. F. A. (2016). Chow, m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature, 537, 369–373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu, J., Yue, Y., Han, D., & Wang, X. (2014). A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nature Chemical Biology, 10, 93–105.

    Article  CAS  PubMed  Google Scholar 

  30. Huang, H., Weng, H., & Chen, J. (2020). The biogenesis and precise control of RNA m(6)A methylation. Trends in Genetics, 36, 44–52.

    Article  CAS  PubMed  Google Scholar 

  31. Huang, H., Weng, H., Zhou, K., & Wu, T. (2019). Histone H3 trimethylation at lysine 36 guides m(6)A RNA modification co-transcriptionally. Nature, 567, 414–419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ping, X. L., Sun, B. F., Wang, L., & Xiao, W. (2014). Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Research, 24, 177–189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, Y., Li, Y., Toth, J. I., & Petroski, M. D. (2014). N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nature Cell Biology, 16, 191–198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schwartz, S., Mumbach, M. R., Jovanovic, M., & Wang, T. (2014). Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5’ sites. Cell Reports, 8, 284–296.

    Article  CAS  PubMed  Google Scholar 

  35. Mendel, M., Chen, K. M., Homolka, D., & Gos, P. (2018). Methylation of structured RNA by the m(6)A writer METTL16 is essential for mouse embryonic development. Molecular Cell, 71, 986–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pendleton, K. E., Chen, B., Liu, K., & Hunter, O. V. (2017). The U6 snRNA m(6)A methyltransferase METTL16 regulates SAM synthetase intron retention. Cell, 169, 824–835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ma, H., & Wang, X. (2019). N(6-)Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation. Nature Chemical Biology, 15, 88–94.

    Article  CAS  PubMed  Google Scholar 

  38. Nvan, T., Ernst, F. G. M., Hawley, B. R., & Zorbas, C. (2019). The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. Nucleic Acids Research, 47, 7719–7733.

    Article  CAS  Google Scholar 

  39. Warda, A. S., Kretschmer, J., Hackert, P., & Lenz, C. (2017). Human METTL16 is a N(6)-methyladenosine (m(6)A) methyltransferase that targets pre-mRNAs and various non-coding RNAs. EMBO Reports, 18, 2004–2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Akichika, S., Hirano, S., & Shichino, Y. (2019). Cap-specific terminal N (6)-methylation of RNA by an RNA polymerase II-associated methyltransferase. Science, 363(64213).

  41. Sun, H., Zhang, M., Li, K., & Bai, D. (2019). Cap-specific, terminal N(6)-methylation by a mammalian m(6)Am methyltransferase. Cell Research, 29, 80–82.

    Article  CAS  PubMed  Google Scholar 

  42. Jia, G., Fu, Y., Zhao, X., & Dai, Q. (2011). N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nature Chemical Biology, 7, 885–887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gerken, T., Girard, C. A., Tung, Y. C., & Webby, C. J. (2007). The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science, 318, 1469–1472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mauer, J., Luo, X., Blanjoie, A., & Jiao, X. (2017). Reversible methylation of m(6)Am in the 5’ cap controls mRNA stability. Nature, 541, 371–375.

    Article  CAS  PubMed  Google Scholar 

  45. Chen, W., Zhang, L., Zheng, G., & Fu, Y. (2014). Crystal structure of the RNA demethylase ALKBH5 from zebrafish. FEBS Letters, 588, 892–898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zheng, G., Dahl, J. A., Niu, Y., & Fedorcsak, P. (2013). ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Molecular Cell, 49, 18–29.

    Article  CAS  PubMed  Google Scholar 

  47. Feng, C., Liu, Y., Wang, G., & Deng, Z. (2014). Crystal structures of the human RNA demethylase Alkbh5 reveal basis for substrate recognition. The Journal of Biological Chemistry, 289, 11571–11583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang, X., Zhao, B. S., Roundtree, I. A., & Lu, Z. (2015). N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell, 161, 1388–1399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Du, H., Zhao, Y., He, J., & Zhang, Y. (2016). YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nature Communications, 7, 12626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Shi, H., Wang, X., Lu, Z., & Zhao, B. S. (2017). YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Research, 27, 315–328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Meyer, K. D., Patil, D. P., Zhou, J., & Zinoviev, A. (2015). 5’ UTR m(6)A promotes Cap-independent translation. Cell, 163, 999–1010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Roundtree, I. A., & He, C. (2016). Nuclear m(6)A reader YTHDC1 regulates mRNA splicing. Trends in Genetics, 32, 320–321.

    Article  CAS  PubMed  Google Scholar 

  53. Roundtree, I. A., Luo, G. Z., Zhang, Z., & Wang, X. (2017). YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs. Elife, 6.

  54. Liu, N., Dai, Q., Zheng, G., He, C., Parisien, M., & Pan, T. (2015). N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature, 518(7540), 560–564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhou, K. I., Shi, H., Lyu, R., Wylder, A. C., Matuszek, Ż., Pan, J. N., et al. (2019). Regulation of co-transcriptional pre-mRNA splicing by m6A through the low-complexity protein hnRNPG. Molecular Cell, 76(1), 70–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Alarcón, C. R., Goodarzi, H., Lee, H., Liu, X., Tavazoie, S., & Tavazoie, S. F. (2015). HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell., 162(6), 1299–1308.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Kehat, I., & Molkentin, J. D. (2010). Molecular pathways underlying cardiac remodeling during pathophysiological stimulation. Circulation, 122, 2727–2735.

    Article  PubMed  Google Scholar 

  58. Li, L., Xu, J., He, L., & Peng, L. (2016). The role of autophagy in cardiac hypertrophy. Acta Biochimica et Biophysica Sinica Shanghai, 48, 491–500.

    Article  CAS  Google Scholar 

  59. Gan, X. T., Zhao, G., Huang, C. X., & Rowe, A. C. (2013). Identification of fat mass and obesity associated (FTO) protein expression in cardiomyocytes: regulation by leptin and its contribution to leptin-induced hypertrophy. PLoS One, 8.

  60. Frangogiannis, N. G. (2019). Cardiac fibrosis: cell biological mechanisms, molecular pathways and therapeutic opportunities. Molecular Aspects of Medicine, 65, 70–99.

    Article  CAS  PubMed  Google Scholar 

  61. González, A., Schelbert, E. B., Díez, J., & Butler, J. (2018). Myocardial interstitial fibrosis in heart failure: biological and translational perspectives. Journal of the American College of Cardiology, 71(15), 1696–1706.

    Article  PubMed  Google Scholar 

  62. Li, T., Zhuang, Y., Yang, W., Xie, Y., Shang, W., Su, S., et al. (2021). Silencing of METTL3 attenuates cardiac fibrosis induced by myocardial infarction via inhibiting the activation of cardiac fibroblasts. The FASEB Journal, 35(2), e21162.

    CAS  PubMed  Google Scholar 

  63. Chen, P. Y., Qin, L., Baeyens, N., & Li, G. (2015). Endothelial-to-mesenchymal transition drives atherosclerosis progression. The Journal of Clinical Investigation, 125, 4514–4528.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Zhang, B. Y., Han, L., Tang, Y. F., Zhang, G. X., Fan, X. L., Zhang, J. J., et al. (2020). METTL14 regulates M6A methylation-modified primary miR-19a to promote cardiovascular endothelial cell proliferation and invasion. European Review for Medical and Pharmacological Sciences, 24(12), 7015–7023.

    PubMed  Google Scholar 

  65. Jian, D., Wang, Y., Jian, L., Tang, H., Rao, L., Chen, K., et al. (2020). METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N6-methyladeosine modifications. Theranostics, 10(20), 8939–8956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Guo, M., Yan, R., Ji, Q., Yao, H., Sun, M., Duan, L., et al. (2020). IFN regulatory Factor-1 induced macrophage pyroptosis by modulating m6A modification of circ_0029589 in patients with acute coronary syndrome. International Immunopharmacology, 86, 106800.

    Article  CAS  PubMed  Google Scholar 

  67. Savarese, G., & Lund, L. H. (2017). Global public health burden of heart failure. Cardiac Failure Review, 3, 7–11.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Azevedo, P. S., Polegato, B. F., Minicucci, M. F., & Paiva, S. A. (2016). Cardiac remodeling: concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment. Arquivos Brasileiros de Cardiologia, 106, 62–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Toischer, K., Rokita, A. G., Unsold, B., & Zhu, W. (2010). Differential cardiac remodeling in preload versus afterload. Circulation, 122, 993–1003.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Yu, R., Li, Q., Feng, Z., & Cai, L. (2019). m6A reader YTHDF2 regulates LPS-induced inflammatory response. International Journal of Molecular Sciences, 20.

  71. Feng, Z., Li, Q., Meng, R., & Yi, B. (2018). METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide-induced inflammatory response in human dental pulp cells. Journal of Cellular and Molecular Medicine, 22, 2558–2568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Berulava T, Buchholz Es, V. Elerdashvili, Pena T. (2020). Changes in m6A RNA methylation contribute to heart failure progression by modulating translation. European Journal of Heart Failure, 22(1), 54-66.

  73. Sun, R., Liu, M., Lu, L., & Zheng, Y. (2015). Congenital heart disease: causes, diagnosis, symptoms, and treatments. Cell Biochemistry and Biophysics, 72, 857–860.

    Article  CAS  PubMed  Google Scholar 

  74. Khoshnood, B., Lelong, N., Houyel, L., & Thieulin, A. C. (2012). Prevalence, timing of diagnosis and mortality of newborns with congenital heart defects: a population-based study. Heart, 98, 1667–1673.

    Article  PubMed  Google Scholar 

  75. Lorzadeh, N., & Kazemirad, N. (2018). Embryonic stem cells and infertility. American Journal of Perinatology, 35, 925–930.

    Article  PubMed  Google Scholar 

  76. Stubbs, S. L., Crook, J. M., Morrison, W. A., & Newcomb, A. E. (2011). Toward clinical application of stem cells for cardiac regeneration. Heart, Lung & Circulation, 20, 173–179.

    Article  Google Scholar 

  77. Fuegemann, C. J., Samraj, A. K., Walsh, & Fleischmann, B. K. (2010). Differentiation of mouse embryonic stem cells into cardiomyocytes via the hanging-drop and mass culture methods. Current Protocols in Stem Cell Biology, 1.

  78. Rupp, S., Zeiher, A. M., Dimmeler, S., & Tonn, T. (2010). A regenerative strategy for heart failure in hypoplastic left heart syndrome: intracoronary administration of autologous bone marrow-derived progenitor cells. The Journal of Heart and Lung Transplantation, 29, 574–577.

    Article  PubMed  Google Scholar 

  79. Slobodin, B., Han, R., Calderone, V., Vrielink, J. A. F. O., Loayza-Puch, F., Elkon, R., et al. (2017). Transcription impacts the efficiency of mRNA translation via co-transcriptional N6-adenosine methylation. Cell, 169(2), 326–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Batista, P. J., Molinie, B., Wang, J., & Qu, K. (2014). m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell, 15, 707–719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kadota, S., Pabon, L., Reinecke, H., & Murry, C. E. (2017). In vivo maturation of human induced pluripotent stem cell-derived cardiomyocytes in neonatal and adult rat hearts. Stem Cell Reports, 8, 278–289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cho, G. S., Lee, D. I., Tampakakis, E., & Murphy, S. (2017). Neonatal transplantation confers maturation of PSC-derived cardiomyocytes conducive to modeling cardiomyopathy. Cell Reports, 18, 571–582.

    Article  CAS  PubMed  Google Scholar 

  83. Skinner, A. C., Perrin, E. M., Moss, L. A., & Skelton, J. A. (2015). Cardiometabolic risks and severity of obesity in children and young adults. The New England Journal of Medicine, 373, 1307–1317.

    Article  PubMed  Google Scholar 

  84. Lavie, C. J., De Schutter, A., Parto, P., & Jahangir, E. (2016). Obesity and prevalence of cardiovascular diseases and prognosis-the obesity paradox updated. Progress in Cardiovascular Diseases, 58, 537–547.

    Article  PubMed  Google Scholar 

  85. Lavie, C. J., Sharma, A., Alpert, M. A., & De Schutter, A. (2016). Update on obesity and obesity paradox in heart failure. Progress in Cardiovascular Diseases, 58, 393–400.

    Article  PubMed  Google Scholar 

  86. Lavie, C. J., Patel, D. A., Milani, R. V., & Ventura, H. O. (2014). Impact of echocardiographic left ventricular geometry on clinical prognosis. Progress in Cardiovascular Diseases, 57, 3–9.

    Article  PubMed  Google Scholar 

  87. Bastien, M., Poirier, P., Lemieux, I., & Despres, J. P. (2014). Overview of epidemiology and contribution of obesity to cardiovascular disease. Progress in Cardiovascular Diseases, 56, 369–381.

    Article  PubMed  Google Scholar 

  88. Ng, M., Fleming, T., Robinson, M., & Thomson, B. (2014). Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet, 384, 766–781.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Heckbert, S. R., Post, W., Pearson, G. D., & Arnett, D. K. (2006). Traditional cardiovascular risk factors in relation to left ventricular mass, volume, and systolic function by cardiac magnetic resonance imaging: the Multiethnic Study of Atherosclerosis. Journal of the American College of Cardiology, 48, 2285–2292.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Santos, A. B., Gupta, D. K., Bello, N. A., & Gori, M. (2016). Prehypertension is associated with abnormalities of cardiac structure and function in the atherosclerosis risk in communities study. American Journal of Hypertension, 29, 568–574.

    Article  CAS  PubMed  Google Scholar 

  91. Haupt, A., Thamer, C., Staiger, H., & Tschritter, O. (2009). Variation in the FTO gene influences food intake but not energy expenditure. Experimental and Clinical Endocrinology & Diabetes, 117, 194–197.

    Article  CAS  Google Scholar 

  92. Cecil, J. E., Tavendale, R., Watt, P., & Hetherington, M. M. (2008). An obesity-associated FTO gene variant and increased energy intake in children. The New England Journal of Medicine, 359, 2558–2566.

    Article  CAS  PubMed  Google Scholar 

  93. Smemo, S., Tena, J. J., Kim, K. H., & Gamazon, E. R. (2014). Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature, 507, 371–375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Claussnitzer, M., Dankel, S. N., Kim, K. H., & Quon, G. (2015). FTO obesity variant circuitry and adipocyte browning in humans. The New England Journal of Medicine, 373, 895–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Stratigopoulos, G., Martin Carli, J. F., O’Day, D. R., & Wang, L. (2014). Hypomorphism for RPGRIP1L, a ciliary gene vicinal to the FTO locus, causes increased adiposity in mice. Cell Metabolism, 19, 767–779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Karra, E., O’Daly, O. G., Choudhury, A. I., & Yousseif, A. (2013). A link between FTO, ghrelin, and impaired brain food-cue responsivity. The Journal of Clinical Investigation, 123, 3539–3551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Melnik, B. C. (2015). Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases. Journal of Translational Medicine, 13, 385.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Fischer, J., Koch, L., Emmerling, C., & Vierkotten, J. (2009). Inactivation of the Fto gene protects from obesity. Nature, 458, 894–898.

    Article  CAS  PubMed  Google Scholar 

  99. Church, C., Moir, L., McMurray, F., & Girard, C. (2010). Overexpression of Fto leads to increased food intake and results in obesity. Nature Genetics, 42, 1086–1092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Liu, C., Mou, S., & Pan, C. (2013). The FTO gene rs9939609 polymorphism predicts risk of cardiovascular disease: a systematic review and meta-analysis. PLoS One, 8.

  101. Fernandes, J. V., Cobucci, R. N., Jatoba, C. A., & Fernandes, T. A. (2015). The role of the mediators of inflammation in cancer development. Pathology Oncology Research, 21, 527–534.

    Article  CAS  PubMed  Google Scholar 

  102. Murata, M. (2018). Inflammation and cancer. Environmental Health and Preventive Medicine, 23, 50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Park, S. B., Park, G. H., Um, Y., & Kim, H. N. (2018). Wood-cultivated ginseng exerts anti-inflammatory effect in LPS-stimulated RAW264.7 cells. International Journal of Biological Macromolecules, 116, 327–334.

    Article  CAS  PubMed  Google Scholar 

  104. Zou, Y. H., Zhao, L., Xu, Y. K., & Bao, J. M. (2018). Anti-inflammatory sesquiterpenoids from the Traditional Chinese Medicine Salvia plebeia: regulates pro-inflammatory mediators through inhibition of NF-kappaB and Erk1/2 signaling pathways in LPS-induced Raw264.7 cells. Journal of Ethnopharmacology, 210, 95–106.

    Article  CAS  PubMed  Google Scholar 

  105. Zou, J., Guo, P., Lv, N., & Huang, D. (2015). Lipopolysaccharide-induced tumor necrosis factor-alpha factor enhances inflammation and is associated with cancer (Review). Molecular Medicine Reports, 12, 6399–6404.

    Article  CAS  PubMed  Google Scholar 

  106. Tabas, I., Garcia-Cardena, G., & Owens, G. K. (2015). Recent insights into the cellular biology of atherosclerosis. The Journal of Cell Biology, 209, 13–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chistiakov, D. A., Melnichenko, A. A., Grechko, A. V., & Myasoedova, V. A. (2018). Potential of anti-inflammatory agents for treatment of atherosclerosis. Experimental and Molecular Pathology, 104, 114–124.

    Article  CAS  PubMed  Google Scholar 

  108. Liu, Y., Yu, H., Zhang, Y., & Zhao, Y. (2008). TLRs are important inflammatory factors in atherosclerosis and may be a therapeutic target. Medical Hypotheses, 70, 314–316.

    Article  CAS  PubMed  Google Scholar 

  109. Rosenson, R. S., Hislop, C., Elliott, M., & Stasiv, Y. (2010). Effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients. Journal of the American College of Cardiology, 56, 1079–1088.

    Article  CAS  PubMed  Google Scholar 

  110. Alaarg, A., Senders, M. L., Varela-Moreira, A., & Perez-Medina, C. (2017). A systematic comparison of clinically viable nanomedicines targeting HMG-CoA reductase in inflammatory atherosclerosis. Journal of Controlled Release, 262, 47–57.

    Article  CAS  PubMed  Google Scholar 

  111. Alaarg, A., Zheng, K. H., van der Valk, F. M., & da Silva, A. E. (2016). Multiple pathway assessment to predict anti-atherogenic efficacy of drugs targeting macrophages in atherosclerotic plaques. Vascular Pharmacology, 82, 51–59.

    Article  CAS  PubMed  Google Scholar 

  112. Tiedje, C., Diaz-Munoz, M. D., Trulley, P., Ahlfors, H., Laass, K., Blackshear, P. J., et al. (2016). The RNAbinding protein TTP is a global post-transcriptional regulator of feedback control in inflammation. Nucleic Acids Research, 44, 7418–7440.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Bulbrook, D., Brazier, H., Mahajan, P., Kliszczak, M., Fedorov, O., Marchese, F. P., et al. (2018). Tryptophan-mediated interactions between tristetraprolin and the CNOT9 subunit are required for CCR4-NOT deadenylase complex recruitment. Journal of Molecular Biology, 430(5), 722–736.

    Article  CAS  PubMed  Google Scholar 

  114. Hafidi, M. E., & Buelna-Chontal, M. (2019). Adipogenesis: a necessary but harmful strategy. International Journal of Molecular Sciences, 20.

  115. Woo, C. Y., Jang, J. E., Lee, S. E., & Koh, E. H. (2019). Mitochondrial dysfunction in adipocytes as a primary cause of adipose tissue inflammation. Diabetes and Metabolism Journal, 43, 247–256.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Rosen, E. D., & MacDougald, O. A. (2006). Adipocyte differentiation from the inside out. Nature Reviews. Molecular Cell Biology, 7, 885–896.

    Article  CAS  PubMed  Google Scholar 

  117. Kobayashi, M., Ohsugi, M., Sasako, T., & Awazawa, M. (2018). The RNA methyltransferase complex of WTAP, METTL3, and METTL14 regulates mitotic clonal expansion in adipogenesis. Molecular and Cellular Biology, 38.

  118. Zhao, X., Yang, Y., Sun, B. F., & Shi, Y. (2014). FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Research, 24, 1403–1419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wu, R., Liu, Y., Yao, Y., & Zhao, Y. (2018). FTO regulates adipogenesis by controlling cell cycle progression via m(6)A-YTHDF2 dependent mechanism. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1863, 1323–1330.

    Article  CAS  PubMed  Google Scholar 

  120. Wang, X., Sun, B., Jiang, Q., & Wu, R. (2018). mRNA m(6)A plays opposite role in regulating UCP2 and PNPLA2 protein expression in adipocytes. International Journal of Obesity, 42, 1912–1924.

    Article  CAS  PubMed  Google Scholar 

  121. Jiang, Q., Sun, B., Liu, Q., & Cai, M. (2019). MTCH2 promotes adipogenesis in intramuscular preadipocytes via an m(6)A-YTHDF1-dependent mechanism. The FASEB Journal, 33, 2971–2981.

    Article  CAS  PubMed  Google Scholar 

  122. Wu, R., Yao, Y., Jiang, Q., & Cai, M. (2018). Epigallocatechin gallate targets FTO and inhibits adipogenesis in an mRNA m(6)A-YTHDF2-dependent manner. International Journal of Obesity, 42, 1378.

    Article  CAS  PubMed  Google Scholar 

  123. Song, T., Yang, Y., Wei, H., & Xie, X. (2019). Zfp217 mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to promote adipogenic differentiation. Nucleic Acids Research, 47, 6130–6144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Liu, Q., Zhao, Y., Wu, R., & Jiang, Q. (2019). ZFP217 regulates adipogenesis by controlling mitotic clonal expansion in a METTL3-m(6)A dependent manner. RNA Biology, 16, 1785–1793.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Budiyani, L., Purnamasari, D., Simadibrata, M., & Abdullah, M. (2018). Insulin resistance in gastroesophageal reflux disease. Acta Medica Indonesiana, 50, 336–342.

    PubMed  Google Scholar 

  126. Salazar, M. R., Carbajal, H. A., Espeche, W. G., & Aizpurua, M. (2016). Insulin resistance: the linchpin between prediabetes and cardiovascular disease. Diabetes & Vascular Disease Research, 131, 157–163.

    Article  CAS  Google Scholar 

  127. Gast, K. B., Tjeerdema, N., Stijnen, T., & Smit, J. W. (2012). Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PLoS One, 7.

  128. Sandeep, S., Gokulakrishnan, K., Deepa, M., & Mohan, V. (2011). Insulin resistance is associated with increased cardiovascular risk in Asian Indians with normal glucose tolerance--the Chennai Urban Rural Epidemiology Study (CURES-66). The Journal of the Association of Physicians of India, 59, 480–484.

    CAS  PubMed  Google Scholar 

  129. Reddy, K. J., Singh, M., Bangit, J. R., & Batsell, R. R. (2010). The role of insulin resistance in the pathogenesis of atherosclerotic cardiovascular disease: an updated review. Journal of Cardiovascular Medicine (Hagerstown, Md.), 11, 633–647.

    Article  Google Scholar 

  130. Ritchie, R. H. (2009). Evidence for a causal role of oxidative stress in the myocardial complications of insulin resistance. Heart, Lung & Circulation, 18, 11–18.

    Article  CAS  Google Scholar 

  131. AlZadjali, M. A., Godfrey, V., Khan, F., & Choy, A. (2009). Insulin resistance is highly prevalent and is associated with reduced exercise tolerance in nondiabetic patients with heart failure. Journal of the American College of Cardiology, 53, 747–753.

    Article  CAS  PubMed  Google Scholar 

  132. Xie, W., Ma, L. L., Xu, Y. Q., & Wang, B. H. (2019). METTL3 inhibits hepatic insulin sensitivity via N6-methyladenosine modification of Fasn mRNA and promoting fatty acid metabolism. Biochemical and Biophysical Research Communications, 518, 120–126.

    Article  CAS  PubMed  Google Scholar 

  133. Iskandar, K., Patria, S. Y., Huriyati, E., & Luglio, H. F. (2018). Effect of FTO rs9939609 variant on insulin resistance in obese female adolescents. BMC Research Notes, 11, 300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Khoshi, A., Bajestani, M. K., Shakeri, H., & Goodarzi, G. (2019). Association of Omentin rs2274907 and FTO rs9939609 gene polymorphisms with insulin resistance in Iranian individuals with newly diagnosed type 2 diabetes. Lipids in Health and Disease, 18, 142.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Han, M., Li, Q., Liu, L., Zhang, D., Ren, Y., Zhao, Y., et al. (2019). Prehypertension and risk of cardiovascular diseases: a meta-analysis of 47 cohort studies. Journal of Hypertension, 37(12), 2325–2332.

    Article  CAS  PubMed  Google Scholar 

  136. Mo, X. B., Lei, S. F., Zhang, Y. H., & Zhang, H. (2019). Examination of the associations between m6A-associated single-nucleotide polymorphisms and blood pressure. Hypertension Research, 42(10), 1582–1589.

    Article  CAS  PubMed  Google Scholar 

  137. Zheng, Y., Nie, P., Peng, D., He, Z., Liu, M., Xie, Y., et al. (2018). m6AVar: a database of functional variants involved in m6A modification. Nucleic Acids Research, 46, D139–D145.

    Article  CAS  PubMed  Google Scholar 

  138. Wu, Q., Yuan, X., Han, R., Zhang, H., & Xiu, R. (2019). Epitranscriptomic mechanisms of N6-methyladenosine methylation regulating mammalian hypertension development by determined spontaneously hypertensive rats pericytes. Epigenomics, 11(12), 1359–1370.

    Article  CAS  PubMed  Google Scholar 

  139. Fox, C. S., Golden, S. H., Anderson, C., Bray, G. A., Burke, L. E., de Boer, I. H., et al. (2015). Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care, 38(9), 1777–1803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Gilbert, E. R., & Liu, D. (2012). Epigenetics: the missing link to understanding β-cell dysfunction in the pathogenesis of type 2 diabetes. Epigenetics, 7(8), 841–852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Shen, F., Huang, W., Huang, J. T., Xiong, J., Yang, Y., Wu, K., et al. (2015). Decreased N(6)-methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5. The Journal of Clinical Endocrinology and Metabolism, 100(1), 148–154.

    Article  CAS  Google Scholar 

  142. Yang, Y., Shen, F., Huang, W., Qin, S., Huang, J. T., Sergi, C., et al. (2019). Glucose is involved in the dynamic regulation of m6A in patients with type 2 diabetes. The Journal of Clinical Endocrinology and Metabolism, 104(3), 665–673.

    Article  PubMed  Google Scholar 

  143. De Jesus, D. F., Zhang, Z., Kahraman, S., Brown, N. K., Chen, M., Hu, J., et al. (2019). m6A mRNA methylation regulates human β-cell biology in physiological states and in type 2 diabetes. Nature Metabolism, 1(8), 765–774.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Xiao, C. L., Zhu, S., He, M., & Chen, D. (2018). N(6)-methyladenine DNA modification in the human genome. Molecular Cell, 71, 306–318.

    Article  CAS  PubMed  Google Scholar 

  145. Koh, C. W. Q., Goh, Y. T., Toh, J. D. W., & Neo, S. P. (2018). Single-nucleotide-resolution sequencing of human N6-methyldeoxyadenosine reveals strand-asymmetric clusters associated with SSBP1 on the mitochondrial genome. Nucleic Acids Research, 46, 11659–11670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Zhang, W., Song, M., Qu, J., & Liu, G. H. (2018). Epigenetic modifications in cardiovascular aging and diseases. Circulation Research, 123, 773–786.

    Article  CAS  PubMed  Google Scholar 

  147. Kim, A. Y., Park, Y. J., Pan, X., & Shin, K. C. (2015). Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance. Nature Communications, 6, 7585.

    Article  PubMed  Google Scholar 

  148. Zhao, J., Goldberg, J., Bremner, J. D., & Vaccarino, V. (2012). Global DNA methylation is associated with insulin resistance: a monozygotic twin study. Diabetes, 61, 542–546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Stenvinkel, P., Karimi, M., Johansson, S., & Axelsson, J. (2007). Impact of inflammation on epigenetic DNA methylation - a novel risk factor for cardiovascular disease? Journal of Internal Medicine, 261, 488–499.

    Article  CAS  PubMed  Google Scholar 

  150. Breton, C. V., Byun, H. M., Wenten, M., & Pan, F. (2009). Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. American Journal of Respiratory and Critical Care Medicine, 180, 462–467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Agha, G., Mendelson, M. M., Ward-Caviness, C. K., & Joehanes, R. (2019). Blood leukocyte DNA methylation predicts risk of future myocardial infarction and coronary heart disease. Circulation, 140, 645–657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Guo, Y., Pei, Y., & Li, C. W. (2020). DNA N(6)-methyladenine modification in hypertension. Aging (Albany NY), 12, 6276–6291.

    Article  CAS  Google Scholar 

  153. Yan, X. C., Cao, J., Liang, L., & Wang, L. (2016). miR-342-5p is a notch downstream molecule and regulates multiple angiogenic pathways including notch, vascular endothelial growth factor and transforming growth factor beta signaling. Journal of the American Heart Association, 5.

  154. Good, R. B., Gilbane, A. J., Trinder, S. L., & Denton, C. P. (2015). Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension. The American Journal of Pathology, 185, 1850–1858.

    Article  CAS  PubMed  Google Scholar 

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Funding

Key Project of Hunan Provincial Department of Education (20A427). This work was supported by the grants from the National Natural Sciences Foundation of China (Nos. 81970390, 82060065), the Natural Science Foundation of Hunan Province (Nos. 2018JJ3455, 2018JJ2341, 2019JJ40249), the Key Project of the Natural Science Foundation of Guangxi Zhuang Autonomous Region, China(No. 2020GXNSFDA297011), the Foundation for Guangxi Key Laboratory of Diabetic Systems Medicine (No. 20-065-77), the Outstanding Young Aid Program for Education Department of Hunan Province (No. 18B274), the Major Project of social science achievement review committee in Hunan Province (No. XSP20ZDI013), and the Hunan Provincial Innovation Foundation For Postgraduate (No. CX20200965).

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Chen, Ys., Ouyang, Xp., Yu, Xh. et al. N6-Adenosine Methylation (m6A) RNA Modification: an Emerging Role in Cardiovascular Diseases. J. of Cardiovasc. Trans. Res. 14, 857–872 (2021). https://doi.org/10.1007/s12265-021-10108-w

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