- 1. Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
- 2. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, P. R. China;
- 3. NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, Sichuan 610041, P. R. China;
- 4. The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
- 5. Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
LIU Hanmin,
Email: liuhm@scu.edu.cn
Pulmonary arterial hypertension (PAH) is a fatal and complex disease characterized by multifactorial involvement in pulmonary vascular remodeling, leading to heart failure. It is difficult to treat and has a poor long-term prognosis. Recent studies highlight the significant role of epigenetic modulation in the pathophysiological progression of PAH, offering new therapeutic approaches to improve clinical outcomes. This article summarizes the role of epigenetic modulation in the development and progression of PAH, focusing on deoxyribonucleic acid methylation, ribonucleic acid methylation, histone modifications, and non-coding ribonucleic acid, in order to understand the role of epigenetic modulation in PAH and identifying new evaluation indexes and therapeutic targets, thereby improving the prognosis of PAH.
Copyright © the editorial department of West China Medical Journal of West China Medical Publisher. All rights reserved
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| 2. | Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J, 2019, 53(1): 1801899. |
| 3. | Kocken JMM, da Costa Martins PA. Epigenetic regulation of pulmonary arterial hypertension-induced vascular and right ventricular remodeling: new opportunities?. Int J Mol Sci, 2020, 21(23): 8901. |
| 4. | Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet, 2018, 19(6): 371-384. |
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| 9. | Xing XQ, Li B, Xu SL, et al. 5-Aza-2’-deoxycytidine, a DNA methylation inhibitor, attenuates hypoxic pulmonary hypertension via demethylation of the PTEN promoter. Eur J Pharmacol, 2019, 855: 227-234. |
| 10. | Perros F, Cohen-Kaminsky S, Gambaryan N, et al. Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmonary veno-occlusive disease. Am J Respir Crit Care Med, 2013, 187(2): 189-196. |
| 11. | Joshi SR, Kitagawa A, Jacob C, et al. Hypoxic activation of glucose-6-phosphate dehydrogenase controls the expression of genes involved in the pathogenesis of pulmonary hypertension through the regulation of DNA methylation. Am J Physiol Lung Cell Mol Physiol, 2020, 318(4): L773-L786. |
| 12. | Wang Y, Huang X, Leng D, et al. DNA methylation signatures of pulmonary arterial smooth muscle cells in chronic thromboembolic pulmonary hypertension. Physiol Genomics, 2018, 50(5): 313-322. |
| 13. | Zhang Y, Zeng C. Role of DNA methylation in cardiovascular diseases. Clin Exp Hypertens, 2016, 38(3): 261-267. |
| 14. | Tao Y, Li G, Yang Y, et al. Epigenomics in aortic dissection: from mechanism to therapeutics. Life Sci, 2023, 335: 122249. |
| 15. | Soubrier F. TET2: a bridge between DNA methylation and vascular inflammation. Circulation, 2020, 141(24): 2001-2003. |
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| 17. | Jiang X, Liu B, Nie Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther, 2021, 6(1): 74. |
| 18. | An Y, Duan H. The role of m6A RNA methylation in cancer metabolism. Mol Cancer, 2022, 21(1): 14. |
| 19. | Sendinc E, Shi Y. RNA m6A methylation across the transcriptome. Mol Cell, 2023, 83(3): 428-441. |
| 20. | Qin Y, Qiao Y, Li L, et al. The m6A methyltransferase METTL3 promotes hypoxic pulmonary arterial hypertension. Life Sci, 2021, 274: 119366. |
| 21. | Xu S, Xu X, Zhang Z, et al. The role of RNA m6A methylation in the regulation of postnatal hypoxia-induced pulmonary hypertension. Respir Res, 2021, 22(1): 121. |
| 22. | Hu L, Wang J, Huang H, et al. YTHDF1 regulates pulmonary hypertension through translational control of MAGED1. Am J Respir Crit Care Med, 2021, 203(9): 1158-1172. |
| 23. | Kang T, Liu L, Tan F, et al. Inhibition of YTHDF1 prevents hypoxia-induced pulmonary artery smooth muscle cell proliferation by regulating Foxm1 translation in an m6A-dependent manner. Exp Cell Res, 2023, 424(2): 113505. |
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| 29. | Xu S, Xu Y, Yin M, et al. Flow-dependent epigenetic regulation of IGFBP5 expression by H3K27me3 contributes to endothelial anti-inflammatory effects. Theranostics, 2018, 8(11): 3007-3021. |
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- 1. Huston JH, Shah SJ. Understanding the pathobiology of pulmonary hypertension due to left heart disease. Circ Res, 2022, 130(9): 1382-1403.
- 2. Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J, 2019, 53(1): 1801899.
- 3. Kocken JMM, da Costa Martins PA. Epigenetic regulation of pulmonary arterial hypertension-induced vascular and right ventricular remodeling: new opportunities?. Int J Mol Sci, 2020, 21(23): 8901.
- 4. Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet, 2018, 19(6): 371-384.
- 5. Yan Y, He YY, Jiang X, et al. DNA methyltransferase 3B deficiency unveils a new pathological mechanism of pulmonary hypertension. Sci Adv, 2020, 6(50): eaba2470.
- 6. Zhang L, Tang L, Wei J, et al. Extrauterine growth restriction on pulmonary vascular endothelial dysfunction in adult male rats: the role of epigenetic mechanisms. J Hypertens, 2014, 32(11): 2188-2198.
- 7. Thenappan T, Ormiston ML, Ryan JJ, et al. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ, 2018, 360: j5492.
- 8. Archer SL, Marsboom G, Kim GH, et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation, 2010, 121(24): 2661-2671.
- 9. Xing XQ, Li B, Xu SL, et al. 5-Aza-2’-deoxycytidine, a DNA methylation inhibitor, attenuates hypoxic pulmonary hypertension via demethylation of the PTEN promoter. Eur J Pharmacol, 2019, 855: 227-234.
- 10. Perros F, Cohen-Kaminsky S, Gambaryan N, et al. Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmonary veno-occlusive disease. Am J Respir Crit Care Med, 2013, 187(2): 189-196.
- 11. Joshi SR, Kitagawa A, Jacob C, et al. Hypoxic activation of glucose-6-phosphate dehydrogenase controls the expression of genes involved in the pathogenesis of pulmonary hypertension through the regulation of DNA methylation. Am J Physiol Lung Cell Mol Physiol, 2020, 318(4): L773-L786.
- 12. Wang Y, Huang X, Leng D, et al. DNA methylation signatures of pulmonary arterial smooth muscle cells in chronic thromboembolic pulmonary hypertension. Physiol Genomics, 2018, 50(5): 313-322.
- 13. Zhang Y, Zeng C. Role of DNA methylation in cardiovascular diseases. Clin Exp Hypertens, 2016, 38(3): 261-267.
- 14. Tao Y, Li G, Yang Y, et al. Epigenomics in aortic dissection: from mechanism to therapeutics. Life Sci, 2023, 335: 122249.
- 15. Soubrier F. TET2: a bridge between DNA methylation and vascular inflammation. Circulation, 2020, 141(24): 2001-2003.
- 16. Wang Z, Zhang YX, Shi JZ, et al. RNA m6A methylation and regulatory proteins in pulmonary arterial hypertension. Hypertens Res, 2024, 47(5): 1273-1287.
- 17. Jiang X, Liu B, Nie Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther, 2021, 6(1): 74.
- 18. An Y, Duan H. The role of m6A RNA methylation in cancer metabolism. Mol Cancer, 2022, 21(1): 14.
- 19. Sendinc E, Shi Y. RNA m6A methylation across the transcriptome. Mol Cell, 2023, 83(3): 428-441.
- 20. Qin Y, Qiao Y, Li L, et al. The m6A methyltransferase METTL3 promotes hypoxic pulmonary arterial hypertension. Life Sci, 2021, 274: 119366.
- 21. Xu S, Xu X, Zhang Z, et al. The role of RNA m6A methylation in the regulation of postnatal hypoxia-induced pulmonary hypertension. Respir Res, 2021, 22(1): 121.
- 22. Hu L, Wang J, Huang H, et al. YTHDF1 regulates pulmonary hypertension through translational control of MAGED1. Am J Respir Crit Care Med, 2021, 203(9): 1158-1172.
- 23. Kang T, Liu L, Tan F, et al. Inhibition of YTHDF1 prevents hypoxia-induced pulmonary artery smooth muscle cell proliferation by regulating Foxm1 translation in an m6A-dependent manner. Exp Cell Res, 2023, 424(2): 113505.
- 24. Wang X, Li Q, He S, et al. LncRNA FENDRR with m6A RNA methylation regulates hypoxia-induced pulmonary artery endothelial cell pyroptosis by mediating DRP1 DNA methylation. Mol Med, 2022, 28(1): 126.
- 25. Oerum S, Meynier V, Catala M, et al. A comprehensive review of m6A/m6Am RNA methyltransferase structures. Nucleic Acids Res, 2021, 49(13): 7239-7255.
- 26. Chelladurai P, Boucherat O, Stenmark K, et al. Targeting histone acetylation in pulmonary hypertension and right ventricular hypertrophy. Br J Pharmacol, 2021, 178(1): 54-71.
- 27. Yang Y, Cheng X, Tian W, et al. MRTF-A steers an epigenetic complex to activate endothelin-induced pro-inflammatory transcription in vascular smooth muscle cells. Nucleic Acids Res, 2014, 42(16): 10460-10472.
- 28. Yan MS, Turgeon PJ, Man HJ, et al. Histone acetyltransferase 7 (KAT7)-dependent intragenic histone acetylation regulates endothelial cell gene regulation. J Biol Chem, 2018, 293(12): 4381-4402.
- 29. Xu S, Xu Y, Yin M, et al. Flow-dependent epigenetic regulation of IGFBP5 expression by H3K27me3 contributes to endothelial anti-inflammatory effects. Theranostics, 2018, 8(11): 3007-3021.
- 30. Khalil AM, Guttman M, Huarte M, et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A, 2009, 106(28): 11667-11672.
- 31. Hulshoff MS, Del Monte-Nieto G, Kovacic J, et al. Non-coding RNA in endothelial-to-mesenchymal transition. Cardiovasc Res, 2019, 115(12): 1716-1731.
- 32. Xiao MS, Ai Y, Wilusz JE. Biogenesis and functions of circular RNAs come into focus. Trends Cell Biol, 2020, 30(3): 226-240.
- 33. Gerthoffer W. Epigenetic targets for oligonucleotide therapies of pulmonary arterial hypertension. Int J Mol Sci, 2020, 21(23): 9222.
- 34. Brock M, Trenkmann M, Gay RE, et al. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type Ⅱ through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res, 2009, 104(10): 1184-1191.
- 35. Caruso P, MacLean MR, Khanin R, et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol, 2010, 30(4): 716-723.
- 36. Bockmeyer CL, Maegel L, Janciauskiene S, et al. Plexiform vasculopathy of severe pulmonary arterial hypertension and microRNA expression. J Heart Lung Transplant, 2012, 31(7): 764-772.
- 37. Caruso P, Dempsie Y, Stevens HC, et al. A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circ Res, 2012, 111(3): 290-300.
- 38. Courboulin A, Paulin R, Giguère NJ, et al. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med, 2011, 208(3): 535-548.
- 39. Meloche J, Le Guen M, Potus F, et al. miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol, 2015, 309(6): C363-C372.
- 40. Wang Y, Yan L, Zhang Z, et al. Epigenetic regulation and its therapeutic potential in pulmonary hypertension. Front Pharmacol, 2018, 9: 241.
- 41. Le Ribeuz H, Courboulin A, Ghigna MR, et al. In vivo miR-138-5p inhibition alleviates monocrotaline-induced pulmonary hypertension and normalizes pulmonary KCNK3 and SLC45A3 expression. Respir Res, 2020, 21(1): 186.
- 42. Miao R, Liu W, Qi C, et al. MiR-18a-5p contributes to enhanced proliferation and migration of PASMCs via targeting Notch2 in pulmonary arterial hypertension. Life Sci, 2020, 257: 117919.
- 43. Zhang R, Su H, Ma X, et al. MiRNA let-7b promotes the development of hypoxic pulmonary hypertension by targeting ACE2. Am J Physiol Lung Cell Mol Physiol, 2019, 316(3): L547-L557.
- 44. Bourgeois A, Bonnet S, Breuils-Bonnet S, et al. Inhibition of CHK 1 (checkpoint kinase 1) elicits therapeutic effects in pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol, 2019, 39(8): 1667-1681.
- 45. Xu YP, He Q, Shen Z, et al. MiR-126a-5p is involved in the hypoxia-induced endothelial-to-mesenchymal transition of neonatal pulmonary hypertension. Hypertens Res, 2017, 40(6): 552-561.
- 46. Wang D, Zhang H, Li M, et al. MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts. Circ Res, 2014, 114(1): 67-78.
- 47. Luo Y, Dong HY, Zhang B, et al. miR-29a-3p attenuates hypoxic pulmonary hypertension by inhibiting pulmonary adventitial fibroblast activation. Hypertension, 2015, 65(2): 414-420.
- 48. Toden S, Zumwalt TJ, Goel A. Non-coding RNAs and potential therapeutic targeting in cancer. Biochim Biophys Acta Rev Cancer, 2021, 1875(1): 188491.
- 49. Gong J, Chen Z, Chen Y, et al. Long non-coding RNA CASC2 suppresses pulmonary artery smooth muscle cell proliferation and phenotypic switch in hypoxia-induced pulmonary hypertension. Respir Res, 2019, 20(1): 53.
- 50. Yang L, Liang H, Shen L, et al. LncRNA Tug1 involves in the pulmonary vascular remodeling in mice with hypoxic pulmonary hypertension via the microRNA-374c-mediated foxc1. Life Sci, 2019, 237: 116769.
- 51. Chinnappan M, Gunewardena S, Chalise P, et al. Analysis of lncRNA-miRNA-mRNA interactions in hyper-proliferative human pulmonary arterial smooth muscle cells. Sci Rep, 2019, 9(1): 10533.
- 52. Su H, Xu X, Yan C, et al. LncRNA H19 promotes the proliferation of pulmonary artery smooth muscle cells through AT1R via sponging let-7b in monocrotaline-induced pulmonary arterial hypertension. Respir Res, 2018, 19(1): 254.
- 53. Zhang H, Liu Y, Yan L, et al. Long noncoding RNA Hoxaas3 contributes to hypoxia-induced pulmonary artery smooth muscle cell proliferation. Cardiovasc Res, 2019, 115(3): 647-657.
- 54. Zhu TT, Sun RL, Yin YL, et al. Long noncoding RNA UCA1 promotes the proliferation of hypoxic human pulmonary artery smooth muscle cells. Pflugers Arch, 2019, 471(2): 347-355.
- 55. Liu X, Li S, Yang Y, et al. The lncRNA ANRIL regulates endothelial dysfunction by targeting the let-7b/TGF-βR1 signalling pathway. J Cell Physiol, 2021, 236(3): 2058-2069.
- 56. Bian W, Jing X, Yang Z, et al. Downregulation of LncRNA NORAD promotes Ox-LDL-induced vascular endothelial cell injury and atherosclerosis. Aging (Albany NY), 2020, 12(7): 6385-6400.
- 57. Jiang Y, Hei B, Hao W, et al. Clinical value of lncRNA SOX2-OT in pulmonary arterial hypertension and its role in pulmonary artery smooth muscle cell proliferation, migration, apoptosis, and inflammatory. Heart Lung, 2022, 55: 16-23.
- 58. Li ZK, Gao LF, Zhu XA, et al. LncRNA HOXA-AS3 promotes the progression of pulmonary arterial hypertension through mediation of miR-675-3p/PDE5A axis. Biochem Genet, 2021, 59(5): 1158-1172.
- 59. Wang H, Qin R, Cheng Y. LncRNA-ang362 promotes pulmonary arterial hypertension by regulating miR-221 and miR-222. Shock, 2020, 53(6): 723-729.
- 60. Liu Y, Sun Z, Zhu J, et al. LncRNA-TCONS_00034812 in cell proliferation and apoptosis of pulmonary artery smooth muscle cells and its mechanism. J Cell Physiol, 2018, 233(6): 4801-4814.
- 61. Xia X, Huang L, Zhou S, et al. Hypoxia-induced long non-coding RNA plasmacytoma variant translocation 1 upregulation aggravates pulmonary arterial smooth muscle cell proliferation by regulating autophagy via miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways. Int J Cardiol, 2023, 370: 368-377.
- 62. Feng X, Wang K, Yang T, et al. LncRNA-GAS5/miR-382-3p axis inhibits pulmonary artery remodeling and promotes autophagy in chronic thromboembolic pulmonary hypertension. Genes Genomics, 2022, 44(4): 395-404.
- 63. Li Y, Zhang J, Sun H, et al. RPS4XL encoded by lnc-Rps4l inhibits hypoxia-induced pyroptosis by binding HSC70 glycosylation site. Mol Ther Nucleic Acids, 2022, 28: 920-934.
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