Skip to main content

Epigenetics and Vascular Disease

Abstract

The mechanisms responsible for vascular disease development have been investigated for many decades, but we are far from a complete identification of all involved molecular processes. This still remains a major unmet need and despite significant improvements in diagnosis, prevention, and early intervention, cardiovascular pathologies are still the leading cause of death and disability worldwide. Epigenetics guides gene expression through the regulation of transcription independently of the genetic code. Those regulatory mechanisms are essential to numerous processes, such as cell growth, development, and differentiation, and they might depend on environmental adaptation, aging, and disease states. The current knowledge on the epigenetic mechanisms regulating vascular physiopathology has uncovered new potential targets for intervention. Herein, we provide an overview of the epigenetic landscape and its role in vascular diseases, highlighting the impact of DNA methylation and histone modification as well as non-coding RNA mechanisms.

Keywords

  • DNA methylation
  • Histone modification
  • Non-coding RNAs
  • Atherosclerosis
  • Vascular diseases
  • Epigenetics
  • Transcription
  • Gene expression

Ignacio Fernando Hall, Montserrat Climent, Floriana Maria Farina have been equally contribute to this work.

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-030-94475-9_20
  • Chapter length: 36 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   189.00
Price excludes VAT (USA)
  • ISBN: 978-3-030-94475-9
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Hardcover Book
USD   249.99
Price excludes VAT (USA)
Fig. 20.1
Fig. 20.2
Fig. 20.3

Abbreviations

5mC:

5-methyl-Cytosine

5-aza:

5-azacytidine

3’UTR:

3′-Untranslated region

circRNA:

Circular RNA

CVD:

Cardiovascular disease

DNMT:

DNA methyltransferase

EC:

Endothelial cell

EndMT:

Endothelial-to-mesenchymal transition

HDL:

High-density lipoprotein

LDL:

Low-density lipoprotein

lncRNA:

Long ncRNA

miRNA, miR:

microRNA

MRE:

miRNA Recognition Element

nt:

Nucleotides

ORF:

Open reading frame

PAH:

Pulmonary artery hypertension

pre-miRNA:

Precursor miRNA

pri-miRNA:

Primary miRNA

PVOD:

Venous-occlusive disease

SNP:

Single nucleotide polymorphism

TSS:

Transcription start site

VSMC:

Vascular smooth muscle cell

References

  1. Murray CJ, Lopez AD (1997) Mortality by cause for eight regions of the world: global burden of disease study. Lancet 349(9061):1269–1276. https://doi.org/10.1016/S0140-6736(96)07493-4

    CAS  CrossRef  PubMed  Google Scholar 

  2. Nabel EG, Braunwald E (2012) A tale of coronary artery disease and myocardial infarction. N Engl J Med 366(1):54–63. https://doi.org/10.1056/NEJMra1112570

    CAS  CrossRef  PubMed  Google Scholar 

  3. Rose G (1964) Familial patterns in ischaemic heart disease. Br J Prev Soc Med 18:75–80. https://doi.org/10.1136/jech.18.2.75

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  4. Sharifi M, Futema M, Nair D, Humphries SE (2017) Genetic architecture of familial hypercholesterolaemia. Curr Cardiol Rep 19(5):44. https://doi.org/10.1007/s11886-017-0848-8

    CrossRef  PubMed  PubMed Central  Google Scholar 

  5. Waddington CH (2012) The epigenotype. 1942. Int J Epidemiol 41(1):10–13. https://doi.org/10.1093/ije/dyr184

    CAS  CrossRef  PubMed  Google Scholar 

  6. H. WC (1956) The genetic assimilation of the bithorax phenotype. Evolution:1–13

    Google Scholar 

  7. Cantone I, Fisher AG (2013) Epigenetic programming and reprogramming during development. Nat Struct Mol Biol 20(3):282–289. https://doi.org/10.1038/nsmb.2489

    CAS  CrossRef  PubMed  Google Scholar 

  8. Lanctôt C, Cheutin T, Cremer M, Cavalli G, Cremer T (2007) Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nat Rev Genet 8(2):104–115. https://doi.org/10.1038/nrg2041

    CAS  CrossRef  PubMed  Google Scholar 

  9. Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429(6990):457–463. https://doi.org/10.1038/nature02625

    CAS  CrossRef  PubMed  Google Scholar 

  10. Quintavalle M, Condorelli G, Elia L (2011) Arterial remodeling and atherosclerosis: miRNAs involvement. Vasc Pharmacol 55(4):106–110. https://doi.org/10.1016/j.vph.2011.08.216S1537-1891(11)00318-1

    CAS  CrossRef  Google Scholar 

  11. van der Harst P, de Windt LJ, Chambers JC (2017) Translational perspective on epigenetics in cardiovascular disease. J Am Coll Cardiol 70(5):590–606. https://doi.org/10.1016/j.jacc.2017.05.067

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  12. Greco CM, Condorelli G (2015) Epigenetic modifications and noncoding RNAs in cardiac hypertrophy and failure. Nat Rev Cardiol 12(8):488–497. https://doi.org/10.1038/nrcardio.2015.71

    CAS  CrossRef  PubMed  Google Scholar 

  13. Cavalli G, Heard E (2019) Advances in epigenetics link genetics to the environment and disease. Nature 571(7766):489–499. https://doi.org/10.1038/s41586-019-1411-0

    CAS  CrossRef  PubMed  Google Scholar 

  14. Suades R, Cosentino F (2019) The environment, epigenetic landscape and cardiovascular risk. Cardiovasc Res 115(13):e147–ee50. https://doi.org/10.1093/cvr/cvz150

    CAS  CrossRef  PubMed  Google Scholar 

  15. Stratton MS, Farina FM, Elia L (2019) Epigenetics and vascular diseases. J Mol Cell Cardiol 133:148–163. https://doi.org/10.1016/j.yjmcc.2019.06.010

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  16. Zarzour A, Kim HW, Weintraub NL (2019) Epigenetic regulation of vascular diseases. Arterioscler Thromb Vasc Biol 39(6):984–990. https://doi.org/10.1161/ATVBAHA.119.312193

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  17. Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S (2009) Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes Care 32(Suppl 2):S314–S321. https://doi.org/10.2337/dc09-S330

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  18. Owens GK, Kumar MS, Wamhoff BR (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84(3):767–801. https://doi.org/10.1152/physrev.00041.2003

    CAS  CrossRef  PubMed  Google Scholar 

  19. Khoury MK, Yang H, Liu B (2020) Macrophage biology in cardiovascular diseases. Arterioscler Thromb Vasc Biol:ATVBAHA120313584. https://doi.org/10.1161/ATVBAHA.120.313584

  20. Basatemur GL, Jørgensen HF, Clarke MCH, Bennett MR, Mallat Z (2019) Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol 16(12):727–744. https://doi.org/10.1038/s41569-019-0227-9

    CrossRef  PubMed  Google Scholar 

  21. Wilson PW, D’Agostino RB, Parise H, Sullivan L, Meigs JB (2005) Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 112(20):3066–3072. https://doi.org/10.1161/CIRCULATIONAHA.105.539528

    CAS  CrossRef  PubMed  Google Scholar 

  22. Fasolo F, Di Gregoli K, Maegdefessel L, Johnson JL (2019) Non-coding RNAs in cardiovascular cell biology and atherosclerosis. Cardiovasc Res 115(12):1732–1756. https://doi.org/10.1093/cvr/cvz203

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  23. Matouk CC, Marsden PA (2008) Epigenetic regulation of vascular endothelial gene expression. Circ Res 102(8):873–887. https://doi.org/10.1161/CIRCRESAHA.107.171025

    CAS  CrossRef  PubMed  Google Scholar 

  24. Chiu JJ, Chien S (2011) Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev 91(1):327–387. https://doi.org/10.1152/physrev.00047.2009

    CrossRef  PubMed  Google Scholar 

  25. Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105(9):1135–1143. https://doi.org/10.1161/hc0902.104353

    CAS  CrossRef  PubMed  Google Scholar 

  26. Cassar A, Holmes DR, Rihal CS, Gersh BJ (2009) Chronic coronary artery disease: diagnosis and management. Mayo Clin Proc 84(12):1130–1146. https://doi.org/10.4065/mcp.2009.0391

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  27. Byrne RA, Joner M, Kastrati A (2015) Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Grüntzig lecture ESC 2014. Eur Heart J 36(47):3320–3331. https://doi.org/10.1093/eurheartj/ehv511

    CrossRef  PubMed  PubMed Central  Google Scholar 

  28. Pierce JB, Feinberg MW (2020) Long noncoding RNAs in atherosclerosis and vascular injury: pathobiology, biomarkers, and targets for therapy. Arterioscler Thromb Vasc Biol 40(9):2002–2017. https://doi.org/10.1161/ATVBAHA.120.314222

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  29. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A et al (2016) 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37(1):67–119. https://doi.org/10.1093/eurheartj/ehv317

    CrossRef  PubMed  Google Scholar 

  30. Ryan JJ, Archer SL (2014) The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure. Circ Res 115(1):176–188. https://doi.org/10.1161/CIRCRESAHA.113.301129

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  31. Lau EMT, Giannoulatou E, Celermajer DS, Humbert M (2017) Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol 14(10):603–614. https://doi.org/10.1038/nrcardio.2017.84

    CAS  CrossRef  PubMed  Google Scholar 

  32. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A et al (2013) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62(25 Suppl):D34–D41. https://doi.org/10.1016/j.jacc.2013.10.029

    CrossRef  PubMed  Google Scholar 

  33. Zahid KR, Raza U, Chen J, Raj UJ, Gou D (2020) Pathobiology of pulmonary artery hypertension: role of long non-coding RNAs. Cardiovasc Res 116(12):1937–1947. https://doi.org/10.1093/cvr/cvaa050

    CAS  CrossRef  PubMed  Google Scholar 

  34. Dejana E, Hirschi KK, Simons M (2017) The molecular basis of endothelial cell plasticity. Nat Commun 8:14361. https://doi.org/10.1038/ncomms14361

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  35. Stenmark KR, Frid MG, Graham BB, Tuder RM (2018) Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension. Cardiovasc Res 114(4):551–564. https://doi.org/10.1093/cvr/cvy004

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  36. Bisserier M, Janostiak R, Lezoualc’h F, Hadri L (2020) Targeting epigenetic mechanisms as an emerging therapeutic strategy in pulmonary hypertension disease. Vasc Biol 2(1):R17–R34. https://doi.org/10.1530/vb-19-0030

    CAS  CrossRef  PubMed  Google Scholar 

  37. Kornberg RD (1974) Chromatin structure: a repeating unit of histones and DNA. Science 184(4139):868–871. https://doi.org/10.1126/science.184.4139.868

    CAS  CrossRef  PubMed  Google Scholar 

  38. Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 a resolution. Nature 389(6648):251–260. https://doi.org/10.1038/38444

    CAS  CrossRef  PubMed  Google Scholar 

  39. Allis CD, Jenuwein T (2016) The molecular hallmarks of epigenetic control. Nat Rev Genet 17(8):487–500. https://doi.org/10.1038/nrg.2016.59

    CAS  CrossRef  PubMed  Google Scholar 

  40. Bird A, Taggart M, Frommer M, Miller OJ, Macleod D (1985) A fraction of the mouse genome that is derived from islands of nonmethylated. CpG-rich DNA Cell 40(1):91–99. https://doi.org/10.1016/0092-8674(85)90312-5

    CAS  CrossRef  PubMed  Google Scholar 

  41. Antequera F, Boyes J, Bird A (1990) High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 62(3):503–514. https://doi.org/10.1016/0092-8674(90)90015-7

    CAS  CrossRef  PubMed  Google Scholar 

  42. Watt F, Molloy PL (1988) Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. Genes Dev 2(9):1136–1143. https://doi.org/10.1101/gad.2.9.1136

    CAS  CrossRef  PubMed  Google Scholar 

  43. Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9(16):2395–2402. https://doi.org/10.1093/hmg/9.16.2395

    CAS  CrossRef  PubMed  Google Scholar 

  44. Yen RW, Vertino PM, Nelkin BD, Yu JJ, el-Deiry W, Cumaraswamy A et al (1992) Isolation and characterization of the cDNA encoding human DNA methyltransferase. Nucleic Acids Res 20(9):2287–2291. https://doi.org/10.1093/nar/20.9.2287

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  45. Hermann A, Goyal R, Jeltsch A (2004) The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J Biol Chem 279(46):48350–48359. https://doi.org/10.1074/jbc.M403427200

    CAS  CrossRef  PubMed  Google Scholar 

  46. Bostick M, Kim JK, Estève PO, Clark A, Pradhan S, Jacobsen SE (2007) UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317(5845):1760–1764. https://doi.org/10.1126/science.1147939

    CAS  CrossRef  PubMed  Google Scholar 

  47. Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99(3):247–257. https://doi.org/10.1016/s0092-8674(00)81656-6

    CAS  CrossRef  PubMed  Google Scholar 

  48. Richard Albert J, Au Yeung WK, Toriyama K, Kobayashi H, Hirasawa R, Brind’Amour J et al (2020) Maternal DNMT3A-dependent de novo methylation of the paternal genome inhibits gene expression in the early embryo. Nat Commun 11(1):5417. https://doi.org/10.1038/s41467-020-19279-7

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  49. Yagi M, Kabata M, Tanaka A, Ukai T, Ohta S, Nakabayashi K et al (2020) Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development. Nat Commun 11(1):3199. https://doi.org/10.1038/s41467-020-16989-w

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  50. Bhutani N, Burns DM, Blau HM (2011) DNA demethylation dynamics. Cell 146(6):866–872. https://doi.org/10.1016/j.cell.2011.08.042

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  51. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324(5929):930–935. https://doi.org/10.1126/science.1170116

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  52. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q et al (2011) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333(6047):1303–1307. https://doi.org/10.1126/science.1210944

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  53. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA et al (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333(6047):1300–1303. https://doi.org/10.1126/science.1210597

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  54. Maiti A, Drohat AC (2011) Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem 286(41):35334–35338. https://doi.org/10.1074/jbc.C111.284620

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  55. Hahn MA, Szabó PE, Pfeifer GP (2014) 5-Hydroxymethylcytosine: a stable or transient DNA modification? Genomics 104(5):314–323. https://doi.org/10.1016/j.ygeno.2014.08.015

    CAS  CrossRef  PubMed  Google Scholar 

  56. Hon GC, Song CX, Du T, Jin F, Selvaraj S, Lee AY et al (2014) 5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. Mol Cell 56(2):286–297. https://doi.org/10.1016/j.molcel.2014.08.026

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  57. Pastor WA, Pape UJ, Huang Y, Henderson HR, Lister R, Ko M et al (2011) Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473(7347):394–397. https://doi.org/10.1038/nature10102

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  58. Jair KW, Bachman KE, Suzuki H, Ting AH, Rhee I, Yen RW et al (2006) De novo CpG island methylation in human cancer cells. Cancer Res 66(2):682–692. https://doi.org/10.1158/0008-5472.CAN-05-1980

    CAS  CrossRef  PubMed  Google Scholar 

  59. Greißel A, Culmes M, Napieralski R, Wagner E, Gebhard H, Schmitt M et al (2015) Alternation of histone and DNA methylation in human atherosclerotic carotid plaques. Thromb Haemost 114(2):390–402. https://doi.org/10.1160/TH14-10-0852

    CrossRef  PubMed  Google Scholar 

  60. Aavik E, Lumivuori H, Leppänen O, Wirth T, Häkkinen SK, Bräsen JH et al (2015) Global DNA methylation analysis of human atherosclerotic plaques reveals extensive genomic hypomethylation and reactivation at imprinted locus 14q32 involving induction of a miRNA cluster. Eur Heart J 36(16):993–1000. https://doi.org/10.1093/eurheartj/ehu437

    CAS  CrossRef  PubMed  Google Scholar 

  61. Valencia-Morales MP, Zaina S, Heyn H, Carmona FJ, Varol N, Sayols S et al (2015) The DNA methylation drift of the atherosclerotic aorta increases with lesion progression. BMC Med Genet 8:7. https://doi.org/10.1186/s12920-015-0085-1

    CAS  CrossRef  Google Scholar 

  62. Zaina S, Heyn H, Carmona FJ, Varol N, Sayols S, Condom E et al (2014) DNA methylation map of human atherosclerosis. Circ Cardiovasc Genet 7(5):692–700. https://doi.org/10.1161/CIRCGENETICS.113.000441

    CAS  CrossRef  PubMed  Google Scholar 

  63. Singh U, Jialal I (2006) Oxidative stress and atherosclerosis. Pathophysiology 13(3):129–142. https://doi.org/10.1016/j.pathophys.2006.05.002

    CAS  CrossRef  PubMed  Google Scholar 

  64. Kim YR, Kim CS, Naqvi A, Kumar A, Kumar S, Hoffman TA et al (2012) Epigenetic upregulation of p66shc mediates low-density lipoprotein cholesterol-induced endothelial cell dysfunction. Am J Physiol Heart Circ Physiol 303(2):H189–H196. https://doi.org/10.1152/ajpheart.01218.2011

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  65. Costantino S, Paneni F, Mitchell K, Mohammed SA, Hussain S, Gkolfos C et al (2018) Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66. Int J Cardiol 268:179–186. https://doi.org/10.1016/j.ijcard.2018.04.082

    CrossRef  PubMed  Google Scholar 

  66. Kumar A, Kumar S, Vikram A, Hoffman TA, Naqvi A, Lewarchik CM et al (2013) Histone and DNA methylation-mediated epigenetic downregulation of endothelial Kruppel-like factor 2 by low-density lipoprotein cholesterol. Arterioscler Thromb Vasc Biol 33(8):1936–1942. https://doi.org/10.1161/ATVBAHA.113.301765

    CAS  CrossRef  PubMed  Google Scholar 

  67. Qi W, Li Q, Liew CW, Rask-Madsen C, Lockhart SM, Rasmussen LM et al (2017) SHP-1 activation inhibits vascular smooth muscle cell proliferation and intimal hyperplasia in a rodent model of insulin resistance and diabetes. Diabetologia 60(3):585–596. https://doi.org/10.1007/s00125-016-4159-1

    CAS  CrossRef  PubMed  Google Scholar 

  68. Kobayashi S, Inoue N, Azumi H, Seno T, Hirata K, Kawashima S et al (2002) Expressional changes of the vascular antioxidant system in atherosclerotic coronary arteries. J Atheroscler Thromb 9(4):184–190. https://doi.org/10.5551/jat.9.184

    CAS  CrossRef  PubMed  Google Scholar 

  69. Weitzman SA, Turk PW, Milkowski DH, Kozlowski K (1994) Free radical adducts induce alterations in DNA cytosine methylation. Proc Natl Acad Sci U S A 91(4):1261–1264. https://doi.org/10.1073/pnas.91.4.1261

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  70. Baccarelli A, Bollati V (2009) Epigenetics and environmental chemicals. Curr Opin Pediatr 21(2):243–251. https://doi.org/10.1097/mop.0b013e32832925cc

    CrossRef  PubMed  PubMed Central  Google Scholar 

  71. Elia L, Kunderfranco P, Carullo P, Vacchiano M, Farina FM, Hall IF et al (2018) UHRF1 epigenetically orchestrates smooth muscle cell plasticity in arterial disease. J Clin Invest 128(6):2473–2486. https://doi.org/10.1172/JCI96121

    CrossRef  PubMed  PubMed Central  Google Scholar 

  72. Thenappan T, Ormiston ML, Ryan JJ, Archer SL (2018) Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ 360:j5492. https://doi.org/10.1136/bmj.j5492

    CrossRef  PubMed  PubMed Central  Google Scholar 

  73. Chelladurai P, Seeger W, Pullamsetti SS (2016) Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives. Eur Respir Rev 25(140):135–140. https://doi.org/10.1183/16000617.0036-2016

    CrossRef  PubMed  Google Scholar 

  74. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thébaud B, Haromy A et al (2006) An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation 113(22):2630–2641. https://doi.org/10.1161/CIRCULATIONAHA.105.609008

    CAS  CrossRef  PubMed  Google Scholar 

  75. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC et al (2010) Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 121(24):2661–2671. https://doi.org/10.1161/CIRCULATIONAHA.109.916098

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  76. Hautefort A, Chesné J, Preussner J, Pullamsetti SS, Tost J, Looso M et al (2017) Pulmonary endothelial cell DNA methylation signature in pulmonary arterial hypertension. Oncotarget 8(32):52995–53016. https://doi.org/10.18632/oncotarget.18031

    CrossRef  PubMed  PubMed Central  Google Scholar 

  77. Yang Q, Lu Z, Ramchandran R, Longo LD, Raj JU (2012) Pulmonary artery smooth muscle cell proliferation and migration in fetal lambs acclimatized to high-altitude long-term hypoxia: role of histone acetylation. Am J Physiol Lung Cell Mol Physiol 303(11):L1001–L1010. https://doi.org/10.1152/ajplung.00092.2012

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  78. Perros F, Cohen-Kaminsky S, Gambaryan N, Girerd B, Raymond N, Klingelschmitt I et al (2013) Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmonary veno-occlusive disease. Am J Respir Crit Care Med 187(2):189–196. https://doi.org/10.1164/rccm.201208-1364OC

    CAS  CrossRef  PubMed  Google Scholar 

  79. Finch JT, Klug A (1976) Solenoidal model for superstructure in chromatin. Proc Natl Acad Sci U S A 73(6):1897–1901. https://doi.org/10.1073/pnas.73.6.1897

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  80. Hergeth SP, Schneider R (2015) The H1 linker histones: multifunctional proteins beyond the nucleosomal core particle. EMBO Rep 16(11):1439–1453. https://doi.org/10.15252/embr.201540749

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  81. Passarge E (1979) Emil Heitz and the concept of heterochromatin: longitudinal chromosome differentiation was recognized fifty years ago. Am J Hum Genet 31(2):106–115

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kouzarides T (2007) Chromatin modifications and their function. Cell 128(4):693–705. https://doi.org/10.1016/j.cell.2007.02.005

    CAS  CrossRef  PubMed  Google Scholar 

  83. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403(6765):41–45. https://doi.org/10.1038/47412

    CAS  CrossRef  PubMed  Google Scholar 

  84. Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6(11):838–849. https://doi.org/10.1038/nrm1761

    CAS  CrossRef  PubMed  Google Scholar 

  85. Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E et al (2011) Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146(6):1016–1028. https://doi.org/10.1016/j.cell.2011.08.008

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  86. Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, Yamada M et al (2004) Histone deimination antagonizes arginine methylation. Cell 118(5):545–553. https://doi.org/10.1016/j.cell.2004.08.020

    CAS  CrossRef  PubMed  Google Scholar 

  87. Eckhart W, Hutchinson MA, Hunter T (1979) An activity phosphorylating tyrosine in polyoma T antigen immunoprecipitates. Cell 18(4):925–933. https://doi.org/10.1016/0092-8674(79)90205-8

    CAS  CrossRef  PubMed  Google Scholar 

  88. Sakabe K, Wang Z, Hart GW (2010) Beta-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proc Natl Acad Sci U S A 107(46):19915–19920. https://doi.org/10.1073/pnas.1009023107

    CrossRef  PubMed  PubMed Central  Google Scholar 

  89. Candau R, Zhou JX, Allis CD, Berger SL (1997) Histone acetyltransferase activity and interaction with ADA2 are critical for GCN5 function in vivo. EMBO J 16(3):555–565. https://doi.org/10.1093/emboj/16.3.555

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  90. Brownell JE, Zhou J, Ranalli T, Kobayashi R, Edmondson DG, Roth SY et al (1996) Tetrahymena histone acetyltransferase a: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84(6):843–851. https://doi.org/10.1016/s0092-8674(00)81063-6

    CAS  CrossRef  PubMed  Google Scholar 

  91. Rosa-Garrido M, Chapski DJ, Vondriska TM (2018) Epigenomes in cardiovascular disease. Circ Res 122(11):1586–1607. https://doi.org/10.1161/CIRCRESAHA.118.311597

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  92. Mu S, Shimosawa T, Ogura S, Wang H, Uetake Y, Kawakami-Mori F et al (2011) Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nat Med 17(5):573–580. https://doi.org/10.1038/nm.2337

    CAS  CrossRef  PubMed  Google Scholar 

  93. Mumby S, Gambaryan N, Meng C, Perros F, Humbert M, Wort SJ et al (2017) Bromodomain and extra-terminal protein mimic JQ1 decreases inflammation in human vascular endothelial cells: implications for pulmonary arterial hypertension. Respirology 22(1):157–164. https://doi.org/10.1111/resp.12872

    CrossRef  PubMed  Google Scholar 

  94. Cho YK, Eom GH, Kee HJ, Kim HS, Choi WY, Nam KI et al (2010) Sodium valproate, a histone deacetylase inhibitor, but not captopril, prevents right ventricular hypertrophy in rats. Circ J 74(4):760–770. https://doi.org/10.1253/circj.cj-09-0580

    CAS  CrossRef  PubMed  Google Scholar 

  95. Yoon S, Eom GH (2016) HDAC and HDAC inhibitor: from cancer to cardiovascular diseases. Chonnam Med J 52(1):1–11. https://doi.org/10.4068/cmj.2016.52.1.1

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  96. Elia L, Condorelli G (2019) The involvement of epigenetics in vascular disease development. Int J Biochem Cell Biol 107:27–31. https://doi.org/10.1016/j.biocel.2018.12.005

    CAS  CrossRef  PubMed  Google Scholar 

  97. Shi X, Hong T, Walter KL, Ewalt M, Michishita E, Hung T et al (2006) ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442(7098):96–99. https://doi.org/10.1038/nature04835

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  98. Costantino S, Paneni F, Cosentino F (2015) Targeting chromatin remodeling to prevent cardiovascular disease in diabetes. Curr Pharm Biotechnol 16(6):531–543. https://doi.org/10.2174/138920101606150407113644

    CAS  CrossRef  PubMed  Google Scholar 

  99. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA et al (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119(7):941–953. https://doi.org/10.1016/j.cell.2004.12.012

    CAS  CrossRef  PubMed  Google Scholar 

  100. Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P et al (2006) Histone demethylation by a family of JmjC domain-containing proteins. Nature 439(7078):811–816. https://doi.org/10.1038/nature04433

    CAS  CrossRef  PubMed  Google Scholar 

  101. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293(5532):1074–1080. https://doi.org/10.1126/science.1063127

    CAS  CrossRef  PubMed  Google Scholar 

  102. Rossetto D, Avvakumov N, Côté J (2012) Histone phosphorylation: a chromatin modification involved in diverse nuclear events. Epigenetics 7(10):1098–1108. https://doi.org/10.4161/epi.21975

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  103. Sawicka A, Seiser C (2014) Sensing core histone phosphorylation—a matter of perfect timing. Biochim Biophys Acta 1839(8):711–718. https://doi.org/10.1016/j.bbagrm.2014.04.013

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  104. Wierda RJ, Rietveld IM, van Eggermond MC, Belien JA, van Zwet EW, Lindeman JH et al (2015) Global histone H3 lysine 27 triple methylation levels are reduced in vessels with advanced atherosclerotic plaques. Life Sci 129:3–9. https://doi.org/10.1016/j.lfs.2014.10.010

    CAS  CrossRef  PubMed  Google Scholar 

  105. Barroso M, Kao D, Blom HJ, Tavares de Almeida I, Castro R, Loscalzo J et al (2016) S-adenosylhomocysteine induces inflammation through NFkB: a possible role for EZH2 in endothelial cell activation. Biochim Biophys Acta 1862(1):82–92. https://doi.org/10.1016/j.bbadis.2015.10.019

    CAS  CrossRef  PubMed  Google Scholar 

  106. Cong G, Yan R, Huang H, Wang K, Yan N, Jin P et al (2017) Involvement of histone methylation in macrophage apoptosis and unstable plaque formation in methionine-induced hyperhomocysteinemic ApoE. Life Sci 173:135–144. https://doi.org/10.1016/j.lfs.2017.02.003

    CAS  CrossRef  PubMed  Google Scholar 

  107. Greißel A, Culmes M, Burgkart R, Zimmermann A, Eckstein HH, Zernecke A et al (2016) Histone acetylation and methylation significantly change with severity of atherosclerosis in human carotid plaques. Cardiovasc Pathol 25(2):79–86. https://doi.org/10.1016/j.carpath.2015.11.001

    CAS  CrossRef  PubMed  Google Scholar 

  108. Manabe I, Owens GK (2001) Recruitment of serum response factor and hyperacetylation of histones at smooth muscle-specific regulatory regions during differentiation of a novel P19-derived in vitro smooth muscle differentiation system. Circ Res 88(11):1127–1134. https://doi.org/10.1161/hh1101.091339

    CAS  CrossRef  PubMed  Google Scholar 

  109. McDonald OG, Wamhoff BR, Hoofnagle MH, Owens GK (2006) Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo. J Clin Invest 116(1):36–48. https://doi.org/10.1172/JCI26505

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  110. Hoeksema MA, Gijbels MJ, Van den Bossche J, van der Velden S, Sijm A, Neele AE et al (2014) Targeting macrophage histone deacetylase 3 stabilizes atherosclerotic lesions. EMBO Mol Med 6(9):1124–1132. https://doi.org/10.15252/emmm.201404170

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  111. Bode KA, Schroder K, Hume DA, Ravasi T, Heeg K, Sweet MJ et al (2007) Histone deacetylase inhibitors decrease toll-like receptor-mediated activation of proinflammatory gene expression by impairing transcription factor recruitment. Immunology 122(4):596–606. https://doi.org/10.1111/j.1365-2567.2007.02678.x

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  112. Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z et al (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448(7154):714–717. https://doi.org/10.1038/nature05987

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  113. Lv YC, Tang YY, Zhang P, Wan W, Yao F, He PP et al (2016) Histone methyltransferase enhancer of Zeste homolog 2-mediated ABCA1 promoter DNA methylation contributes to the progression of atherosclerosis. PLoS One 11(6):e0157265. https://doi.org/10.1371/journal.pone.0157265

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  114. Wang Y, Huang XX, Leng D, Li JF, Liang Y, Jiang T (2021) Effect of EZH2 on pulmonary artery smooth muscle cell migration in pulmonary hypertension. Mol Med Rep 23(2):1. https://doi.org/10.3892/mmr.2020.11768

    CAS  CrossRef  Google Scholar 

  115. Chen D, Yang Y, Cheng X, Fang F, Xu G, Yuan Z et al (2015) Megakaryocytic leukemia 1 directs a histone H3 lysine 4 methyltransferase complex to regulate hypoxic pulmonary hypertension. Hypertension 65(4):821–833. https://doi.org/10.1161/HYPERTENSIONAHA.114.04585

    CAS  CrossRef  PubMed  Google Scholar 

  116. Zhou XL, Liu ZB, Zhu RR, Huang H, Xu QR, Xu H et al (2019) NSD2 silencing alleviates pulmonary arterial hypertension by inhibiting trehalose metabolism and autophagy. Clin Sci (Lond) 133(9):1085–1096. https://doi.org/10.1042/CS20190142

    CAS  CrossRef  Google Scholar 

  117. Chelladurai P, Dabral S, Basineni SR, Chen CN, Schmoranzer M, Bender N et al (2020) Isoform-specific characterization of class I histone deacetylases and their therapeutic modulation in pulmonary hypertension. Sci Rep 10(1):12864. https://doi.org/10.1038/s41598-020-69737-x

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  118. Xu XF, Lv Y, Gu WZ, Tang LL, Wei JK, Zhang LY et al (2013) Epigenetics of hypoxic pulmonary arterial hypertension following intrauterine growth retardation rat: epigenetics in PAH following IUGR. Respir Res 14:20. https://doi.org/10.1186/1465-9921-14-20

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  119. Cardinale JP, Sriramula S, Pariaut R, Guggilam A, Mariappan N, Elks CM et al (2010) HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats. Hypertension 56(3):437–444. https://doi.org/10.1161/HYPERTENSIONAHA.110.154567

    CAS  CrossRef  PubMed  Google Scholar 

  120. Lee HA, Lee DY, Cho HM, Kim SY, Iwasaki Y, Kim IK (2013) Histone deacetylase inhibition attenuates transcriptional activity of mineralocorticoid receptor through its acetylation and prevents development of hypertension. Circ Res 112(7):1004–1012. https://doi.org/10.1161/CIRCRESAHA.113.301071

    CAS  CrossRef  PubMed  Google Scholar 

  121. Usui T, Okada M, Mizuno W, Oda M, Ide N, Morita T et al (2012) HDAC4 mediates development of hypertension via vascular inflammation in spontaneous hypertensive rats. Am J Physiol Heart Circ Physiol 302(9):H1894–H1904. https://doi.org/10.1152/ajpheart.01039.2011

    CAS  CrossRef  PubMed  Google Scholar 

  122. Kim J, Hwangbo C, Hu X, Kang Y, Papangeli I, Mehrotra D et al (2015) Restoration of impaired endothelial myocyte enhancer factor 2 function rescues pulmonary arterial hypertension. Circulation 131(2):190–199. https://doi.org/10.1161/CIRCULATIONAHA.114.013339

    CrossRef  PubMed  Google Scholar 

  123. Nozik-Grayck E, Woods C, Stearman RS, Venkataraman S, Ferguson BS, Swain K et al (2016) Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 311(1):L124–L134. https://doi.org/10.1152/ajplung.00263.2015

    CrossRef  PubMed  PubMed Central  Google Scholar 

  124. Xu X, Ha CH, Wong C, Wang W, Hausser A, Pfizenmaier K et al (2007) Angiotensin II stimulates protein kinase D-dependent histone deacetylase 5 phosphorylation and nuclear export leading to vascular smooth muscle cell hypertrophy. Arterioscler Thromb Vasc Biol 27(11):2355–2362. https://doi.org/10.1161/ATVBAHA.107.151704

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  125. Fiedler J, Baker AH, Dimmeler S, Heymans S, Mayr M, Thum T (2018) Non-coding RNAs in vascular disease—from basic science to clinical applications: scientific update from the working Group of Myocardial Function of the European Society of Cardiology. Cardiovasc Res 114(10):1281–1286. https://doi.org/10.1093/cvr/cvy121

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  126. Wapinski O, Chang HY (2011) Long noncoding RNAs and human disease. Trends Cell Biol 21(6):354–361. https://doi.org/10.1016/j.tcb.2011.04.001

    CAS  CrossRef  PubMed  Google Scholar 

  127. Poller W, Dimmeler S, Heymans S, Zeller T, Haas J, Karakas M et al (2018) Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives. Eur Heart J 39(29):2704–2716. https://doi.org/10.1093/eurheartj/ehx165

    CAS  CrossRef  PubMed  Google Scholar 

  128. Pagiatakis C, Hall IF, Condorelli G (2020) Long non-coding RNA H19: a new avenue for RNA therapeutics in cardiac hypertrophy? Eur Heart J 41(36):3475–3476. https://doi.org/10.1093/eurheartj/ehaa663

    CrossRef  PubMed  Google Scholar 

  129. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233. https://doi.org/10.1016/j.cell.2009.01.002

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  130. Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10(3):155–159. https://doi.org/10.1038/nrg2521

    CAS  CrossRef  PubMed  Google Scholar 

  131. Quinn JJ, Chang HY (2016) Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17(1):47–62. https://doi.org/10.1038/nrg.2015.10

    CAS  CrossRef  PubMed  Google Scholar 

  132. Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, 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

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  133. 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

    CAS  CrossRef  PubMed  Google Scholar 

  134. Barrett SP, Salzman J (2016) Circular RNAs: analysis, expression and potential functions. Development 143(11):1838–1847. https://doi.org/10.1242/dev.128074

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  135. Elia L, Condorelli G (2015) RNA (epi)genetics in cardiovascular diseases. J Mol Cell Cardiol 89(Pt A):11–16. https://doi.org/10.1016/j.yjmcc.2015.07.012

    CAS  CrossRef  PubMed  Google Scholar 

  136. Beerman I, Rossi DJ (2015) Epigenetic control of stem cell potential during homeostasis, aging, and disease. Cell Stem Cell 16(6):613–625. https://doi.org/10.1016/j.stem.2015.05.009

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  137. Elia L, Quintavalle M (2017) Epigenetics and vascular diseases: influence of non-coding RNAs and their clinical implications. Front Cardiovasc Med 4:26. https://doi.org/10.3389/fcvm.2017.00026

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  138. Uchida S, Dimmeler S (2015) Long noncoding RNAs in cardiovascular diseases. Circ Res 116(4):737–750. https://doi.org/10.1161/CIRCRESAHA.116.302521

    CAS  CrossRef  PubMed  Google Scholar 

  139. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297

    CAS  CrossRef  PubMed  Google Scholar 

  140. Lopez-Pedrera C, Barbarroja N, Patiño-Trives AM, Luque-Tévar M, Torres-Granados C, Aguirre-Zamorano MA et al (2020) Role of microRNAs in the development of cardiovascular disease in systemic autoimmune disorders. Int J Mol Sci 21(6). https://doi.org/10.3390/ijms21062012

  141. O’Brien J, Hayder H, Zayed Y, Peng C (2018) Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol (Lausanne) 9:402. https://doi.org/10.3389/fendo.2018.00402

    CrossRef  Google Scholar 

  142. Ghini F, Rubolino C, Climent M, Simeone I, Marzi MJ, Nicassio F (2018) Endogenous transcripts control miRNA levels and activity in mammalian cells by target-directed miRNA degradation. Nat Commun 9(1):3119. https://doi.org/10.1038/s41467-018-05182-9

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  143. Shukla GC, Singh J, Barik S (2011) MicroRNAs: processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol 3(3):83–92

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Statello L, Guo CJ, Chen LL, Huarte M (2021) Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol 22(2):96–118. https://doi.org/10.1038/s41580-020-00315-9

    CAS  CrossRef  PubMed  Google Scholar 

  145. Erdmann VA, Szymanski M, Hochberg A, de Groot N, Barciszewski J (1999) Collection of mRNA-like non-coding RNAs. Nucleic Acids Res 27(1):192–195. https://doi.org/10.1093/nar/27.1.192

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  146. Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT et al (2007) RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316(5830):1484–1488. https://doi.org/10.1126/science.1138341

    CAS  CrossRef  PubMed  Google Scholar 

  147. Salamon I, Saccani Jotti G, Condorelli G (2018) The long noncoding RNA landscape in cardiovascular disease: a brief update. Curr Opin Cardiol 33(3):282–289. https://doi.org/10.1097/HCO.0000000000000507

    CrossRef  PubMed  Google Scholar 

  148. Yuan Y, Xu L, Geng Z, Liu J, Zhang L, Wu Y et al (2021) The role of non-coding RNA network in atherosclerosis. Life Sci 265:118756. https://doi.org/10.1016/j.lfs.2020.118756

    CAS  CrossRef  PubMed  Google Scholar 

  149. Pang KC, Frith MC, Mattick JS (2006) Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function. Trends Genet 22(1):1–5. https://doi.org/10.1016/j.tig.2005.10.003

    CAS  CrossRef  PubMed  Google Scholar 

  150. Leeper NJ, Maegdefessel L (2018) Non-coding RNAs: key regulators of smooth muscle cell fate in vascular disease. Cardiovasc Res 114(4):611–621. https://doi.org/10.1093/cvr/cvx249

    CAS  CrossRef  PubMed  Google Scholar 

  151. Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A et al (2011) Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 25(18):1915–1927. https://doi.org/10.1101/gad.17446611

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  152. Boon RA, Jaé N, Holdt L, Dimmeler S (2016) Long noncoding RNAs: from clinical genetics to therapeutic targets? J Am Coll Cardiol 67(10):1214–1226. https://doi.org/10.1016/j.jacc.2015.12.051

    CAS  CrossRef  PubMed  Google Scholar 

  153. Guttman M, Rinn JL (2012) Modular regulatory principles of large non-coding RNAs. Nature 482(7385):339–346. https://doi.org/10.1038/nature10887

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  154. Pagiatakis C, Musolino E, Gornati R, Bernardini G, Papait R (2019) Epigenetics of aging and disease: a brief overview. Aging Clin Exp Res. https://doi.org/10.1007/s40520-019-01430-0

  155. Soler-Botija C, Gálvez-Montón C, Bayés-Genís A (2019) Epigenetic biomarkers in cardiovascular diseases. Front Genet 10:950. https://doi.org/10.3389/fgene.2019.00950

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

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

    CAS  CrossRef  PubMed  Google Scholar 

  157. Lim TB, Lavenniah A, Foo RS (2020) Circles in the heart and cardiovascular system. Cardiovasc Res 116(2):269–278. https://doi.org/10.1093/cvr/cvz227

    CAS  CrossRef  PubMed  Google Scholar 

  158. Aranda JF, Madrigal-Matute J, Rotllan N, Fernández-Hernando C (2013) MicroRNA modulation of lipid metabolism and oxidative stress in cardiometabolic diseases. Free Radic Biol Med 64:31–39. https://doi.org/10.1016/j.freeradbiomed.2013.07.014

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  159. Romaine SP, Tomaszewski M, Condorelli G, Samani NJ (2015) MicroRNAs in cardiovascular disease: an introduction for clinicians. Heart 101(12):921–928. https://doi.org/10.1136/heartjnl-2013-305402

    CAS  CrossRef  PubMed  Google Scholar 

  160. Nishiguchi T, Imanishi T, Akasaka T (2015) MicroRNAs and cardiovascular diseases. Biomed Res Int 2015:682857. https://doi.org/10.1155/2015/682857

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  161. Collura S, Morsiani C, Vacirca A, Fronterrè S, Ciavarella C, Vasuri F et al (2020) The carotid plaque as paradigmatic case of site-specific acceleration of aging process: the microRNAs and the inflammaging contribution. Ageing Res Rev 61:101090. https://doi.org/10.1016/j.arr.2020.101090

    CAS  CrossRef  PubMed  Google Scholar 

  162. Madrigal-Matute J, Rotllan N, Aranda JF, Fernández-Hernando C (2013) MicroRNAs and atherosclerosis. Curr Atheroscler Rep 15(5):322. https://doi.org/10.1007/s11883-013-0322-z

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  163. Li C, Li S, Zhang F, Wu M, Liang H, Song J et al (2018) Endothelial microparticles-mediated transfer of microRNA-19b promotes atherosclerosis via activating perivascular adipose tissue inflammation in apoE. Biochem Biophys Res Commun 495(2):1922–1929. https://doi.org/10.1016/j.bbrc.2017.11.195

    CAS  CrossRef  PubMed  Google Scholar 

  164. Jamaluddin MS, Weakley SM, Zhang L, Kougias P, Lin PH, Yao Q et al (2011) miRNAs: roles and clinical applications in vascular disease. Expert Rev Mol Diagn 11(1):79–89. https://doi.org/10.1586/erm.10.103

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  165. Lu Y, Thavarajah T, Gu W, Cai J, Xu Q (2018) Impact of miRNA in atherosclerosis. Arterioscler Thromb Vasc Biol 38(9):e159–ee70. https://doi.org/10.1161/ATVBAHA.118.310227

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  166. Farina FM, Hall IF, Serio S, Zani S, Climent M, Salvarani N et al (2020) miR-128-3p is a novel regulator of vascular smooth muscle cell phenotypic switch and vascular diseases. Circ Res 126(12):e120–ee35. https://doi.org/10.1161/CIRCRESAHA.120.316489

    CAS  CrossRef  PubMed  Google Scholar 

  167. Holdt LM, Hoffmann S, Sass K, Langenberger D, Scholz M, Krohn K et al (2013) Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks. PLoS Genet 9(7):e1003588. https://doi.org/10.1371/journal.pgen.1003588

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  168. Kotake Y, Nakagawa T, Kitagawa K, Suzuki S, Liu N, Kitagawa M et al (2011) Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene 30(16):1956–1962. https://doi.org/10.1038/onc.2010.568

    CAS  CrossRef  PubMed  Google Scholar 

  169. Holdt LM, Beutner F, Scholz M, Gielen S, Gäbel G, Bergert H et al (2010) ANRIL expression is associated with atherosclerosis risk at chromosome 9p21. Arterioscler Thromb Vasc Biol 30(3):620–627. https://doi.org/10.1161/ATVBAHA.109.196832

    CAS  CrossRef  PubMed  Google Scholar 

  170. Congrains A, Kamide K, Oguro R, Yasuda O, Miyata K, Yamamoto E et al (2012) Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B. Atherosclerosis 220(2):449–455. https://doi.org/10.1016/j.atherosclerosis.2011.11.017

    CAS  CrossRef  PubMed  Google Scholar 

  171. Kurian L, Aguirre A, Sancho-Martinez I, Benner C, Hishida T, Nguyen TB et al (2015) Identification of novel long noncoding RNAs underlying vertebrate cardiovascular development. Circulation 131(14):1278–1290. https://doi.org/10.1161/CIRCULATIONAHA.114.013303

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  172. Miao Y, Ajami NE, Huang TS, Lin FM, Lou CH, Wang YT et al (2018) Enhancer-associated long non-coding RNA LEENE regulates endothelial nitric oxide synthase and endothelial function. Nat Commun 9(1):292. https://doi.org/10.1038/s41467-017-02113-y

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  173. Robb GB, Carson AR, Tai SC, Fish JE, Singh S, Yamada T et al (2004) Post-transcriptional regulation of endothelial nitric-oxide synthase by an overlapping antisense mRNA transcript. J Biol Chem 279(36):37982–37996. https://doi.org/10.1074/jbc.M400271200

    CAS  CrossRef  PubMed  Google Scholar 

  174. Fiedler J, Breckwoldt K, Remmele CW, Hartmann D, Dittrich M, Pfanne A et al (2015) Development of Long noncoding RNA-based strategies to modulate tissue vascularization. J Am Coll Cardiol 66(18):2005–2015. https://doi.org/10.1016/j.jacc.2015.07.081

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  175. Boeckel JN, Jaé N, Heumüller AW, Chen W, Boon RA, Stellos K et al (2015) Identification and characterization of hypoxia-regulated endothelial circular RNA. Circ Res 117(10):884–890. https://doi.org/10.1161/CIRCRESAHA.115.306319

    CAS  CrossRef  PubMed  Google Scholar 

  176. Michalik KM, You X, Manavski Y, Doddaballapur A, Zörnig M, Braun T et al (2014) Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res 114(9):1389–1397. https://doi.org/10.1161/CIRCRESAHA.114.303265

    CAS  CrossRef  PubMed  Google Scholar 

  177. Cremer S, Michalik KM, Fischer A, Pfisterer L, Jaé N, Winter C et al (2019) Hematopoietic deficiency of the Long noncoding RNA MALAT1 promotes atherosclerosis and plaque inflammation. Circulation 139(10):1320–1334. https://doi.org/10.1161/CIRCULATIONAHA.117.029015

    CAS  CrossRef  PubMed  Google Scholar 

  178. Bell RD, Long X, Lin M, Bergmann JH, Nanda V, Cowan SL et al (2014) Identification and initial functional characterization of a human vascular cell-enriched long noncoding RNA. Arterioscler Thromb Vasc Biol 34(6):1249–1259. https://doi.org/10.1161/ATVBAHA.114.303240

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  179. Lyu Q, Xu S, Lyu Y, Choi M, Christie CK, Slivano OJ et al (2019) Stabilizes vascular endothelial cell adherens junctions through interaction with CKAP4. Proc Natl Acad Sci U S A 116(2):546–555. https://doi.org/10.1073/pnas.1810729116

    CAS  CrossRef  PubMed  Google Scholar 

  180. Boulberdaa M, Scott E, Ballantyne M, Garcia R, Descamps B, Angelini GD et al (2016) A role for the Long noncoding RNA SENCR in commitment and function of endothelial cells. Mol Ther 24(5):978–990. https://doi.org/10.1038/mt.2016.41

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  181. Hall IF, Climent M, Quintavalle M, Farina FM, 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. Circ Res 124(4):498–510. https://doi.org/10.1161/CIRCRESAHA.118.314240

    CAS  CrossRef  PubMed  Google Scholar 

  182. Liu X, Cheng Y, Yang J, Xu L, Zhang C (2012) Cell-specific effects of miR-221/222 in vessels: molecular mechanism and therapeutic application. J Mol Cell Cardiol 52(1):245–255. https://doi.org/10.1016/j.yjmcc.2011.11.008

    CAS  CrossRef  PubMed  Google Scholar 

  183. Leung A, Trac C, Jin W, Lanting L, Akbany A, Sætrom P et al (2013) Novel long noncoding RNAs are regulated by angiotensin II in vascular smooth muscle cells. Circ Res 113(3):266–278. https://doi.org/10.1161/CIRCRESAHA.112.300849

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  184. Mahmoud AD, Ballantyne MD, Miscianinov V, Pinel K, Hung J, Scanlon JP et al (2019) The human-specific and smooth muscle cell-enriched LncRNA SMILR promotes proliferation by regulating mitotic CENPF mRNA and drives cell-cycle progression which can be targeted to limit vascular Remodeling. Circ Res 125(5):535–551. https://doi.org/10.1161/CIRCRESAHA.119.314876

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  185. Ye ZM, Yang S, Xia YP, Hu RT, Chen S, Li BW et al (2019) LncRNA MIAT sponges miR-149-5p to inhibit efferocytosis in advanced atherosclerosis through CD47 upregulation. Cell Death Dis 10(2):138. https://doi.org/10.1038/s41419-019-1409-4

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  186. Hung J, Scanlon JP, Mahmoud AD, Rodor J, Ballantyne M, Fontaine MAC et al (2020) Novel plaque enriched Long noncoding RNA in atherosclerotic macrophage regulation (PELATON). Arterioscler Thromb Vasc Biol 40(3):697–713. https://doi.org/10.1161/ATVBAHA.119.313430

    CAS  CrossRef  PubMed  Google Scholar 

  187. Sun C, Fu Y, Gu X, Xi X, Peng X, Wang C et al (2020) Macrophage-enriched lncRNA RAPIA: a novel therapeutic target for atherosclerosis. Arterioscler Thromb Vasc Biol 40(6):1464–1478. https://doi.org/10.1161/ATVBAHA.119.313749

    CAS  CrossRef  PubMed  Google Scholar 

  188. Gast M, Rauch BH, Nakagawa S, Haghikia A, Jasina A, Haas J et al (2019) Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE−/−mice. Cardiovasc Res 115(2):302–314. https://doi.org/10.1093/cvr/cvy202

    CAS  CrossRef  PubMed  Google Scholar 

  189. Courboulin A, Paulin R, Giguère NJ, Saksouk N, Perreault T, Meloche J et al (2011) Role for miR-204 in human pulmonary arterial hypertension. J Exp Med 208(3):535–548. https://doi.org/10.1084/jem.20101812

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  190. Tanzer A, Stadler PF (2004) Molecular evolution of a microRNA cluster. J Mol Biol 339(2):327–335. https://doi.org/10.1016/j.jmb.2004.03.065

    CAS  CrossRef  PubMed  Google Scholar 

  191. Chen T, Zhou G, Zhou Q, Tang H, Ibe JC, Cheng H et al (2015) Loss of microRNA-17∼92 in smooth muscle cells attenuates experimental pulmonary hypertension via induction of PDZ and LIM domain 5. Am J Respir Crit Care Med 191(6):678–692. https://doi.org/10.1164/rccm.201405-0941OC

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  192. Elia L, Quintavalle M, Zhang J, Contu R, Cossu L, Latronico MV et al (2009) The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease. Cell Death Differ 16(12):1590–1598. https://doi.org/10.1038/cdd.2009.153

    CAS  CrossRef  PubMed  Google Scholar 

  193. Caruso P, Dempsie Y, Stevens HC, McDonald RA, Long L, Lu R et al (2012) A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circ Res 111(3):290–300. https://doi.org/10.1161/CIRCRESAHA.112.267591

    CAS  CrossRef  PubMed  Google Scholar 

  194. Davis-Dusenbery BN, Chan MC, Reno KE, Weisman AS, Layne MD, Lagna G et al (2011) Down-regulation of Kruppel-like factor-4 (KLF4) by microRNA-143/145 is critical for modulation of vascular smooth muscle cell phenotype by transforming growth factor-beta and bone morphogenetic protein 4. J Biol Chem 286(32):28097–28110. https://doi.org/10.1074/jbc.M111.236950

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  195. Li W, Dunmore BJ, Morrell NW (2010) Bone morphogenetic protein type II receptor mutations causing protein misfolding in heritable pulmonary arterial hypertension. Proc Am Thorac Soc 7(6):395–398. https://doi.org/10.1513/pats.201002-024AW

    CAS  CrossRef  PubMed  Google Scholar 

  196. Brock M, Trenkmann M, Gay RE, Michel BA, Gay S, Fischler M et al (2009) Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res 104(10):1184–1191. https://doi.org/10.1161/CIRCRESAHA.109.197491

    CAS  CrossRef  PubMed  Google Scholar 

  197. Zhang J, He Y, Yan X, Chen S, He M, Lei Y et al (2020) MicroRNA-483 amelioration of experimental pulmonary hypertension. EMBO Mol Med 12(5):e11303. https://doi.org/10.15252/emmm.201911303

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  198. Neumann P, Jaé N, Knau A, Glaser SF, Fouani Y, Rossbach O et al (2018) The lncRNA GATA6-AS epigenetically regulates endothelial gene expression via interaction with LOXL2. Nat Commun 9(1):237. https://doi.org/10.1038/s41467-017-02431-1

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  199. Voellenkle C, Garcia-Manteiga JM, Pedrotti S, Perfetti A, De Toma I, Da Silva D et al (2016) Implication of Long noncoding RNAs in the endothelial cell response to hypoxia revealed by RNA-sequencing. Sci Rep 6:24141. https://doi.org/10.1038/srep24141

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  200. Zhang H, Liu Y, Yan L, Wang S, Zhang M, Ma C et al (2019) Long noncoding RNA Hoxaas3 contributes to hypoxia-induced pulmonary artery smooth muscle cell proliferation. Cardiovasc Res 115(3):647–657. https://doi.org/10.1093/cvr/cvy250

    CAS  CrossRef  PubMed  Google Scholar 

  201. Chen J, Guo J, Cui X, Dai Y, Tang Z, Qu J et al (2018) The Long noncoding RNA LnRPT is regulated by PDGF-BB and modulates the proliferation of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol 58(2):181–193. https://doi.org/10.1165/rcmb.2017-0111OC

    CAS  CrossRef  PubMed  Google Scholar 

  202. Su H, Xu X, Yan C, Shi Y, Hu Y, Dong L et al (2018) LncRNA H19 promotes the proliferation of pulmonary artery smooth muscle cells through AT. Respir Res 19(1):254. https://doi.org/10.1186/s12931-018-0956-z

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  203. Carpenter S, Aiello D, Atianand MK, Ricci EP, Gandhi P, Hall LL et al (2013) A long noncoding RNA mediates both activation and repression of immune response genes. Science 341(6147):789–792. https://doi.org/10.1126/science.1240925

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  204. Cheng G, He L, Zhang Y (2020) LincRNA-Cox2 promotes pulmonary arterial hypertension by regulating the let-7a-mediated STAT3 signaling pathway. Mol Cell Biochem 475(1–2):239–247. https://doi.org/10.1007/s11010-020-03877-6

    CAS  CrossRef  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by grants from the Horizon 2020 Research and Innovation Program under Grant Agreement (No. 828984), the Italian Ministry of Health (No. GR-2016-02364133), and Italian Ministry of Research (No. 2017HTKLRF) to L.E.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Leonardo Elia .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Verify currency and authenticity via CrossMark

Cite this chapter

Hall, I.F., Climent, M., Farina, F.M., Elia, L. (2022). Epigenetics and Vascular Disease. In: Michels, K.B. (eds) Epigenetic Epidemiology. Springer, Cham. https://doi.org/10.1007/978-3-030-94475-9_20

Download citation