Epigenetic Mechanisms Affecting the Development of Atherosclerosis: A Narrative Review

Document Type : Narrative Review

Authors

Department of Biotechnology, Institute of Science and High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman, Iran.

Abstract

Introduction: Atherosclerosis is a chronic inflammatory arterial disease that underlies several cardiovascular conditions, including coronary artery disease, heart failure, and stroke. A hallmark of atherosclerosis is the accumulation of fatty plaques, involving various cell types and molecular pathways. The development of this disease involves complex interactions between genetic and environmental factors.
Materials and Methods:  A review was conducted using bibliographic databases such as PubMed and Scopus to examine articles on epigenetic alterations and their impact on atherosclerosis and cardiovascular disease. Furthermore, in silico data analyses related to epigenetics and atherosclerosis were also performed.
Results: Epigenetic processes, including DNA methylation, histone modifications, and non-coding RNA, are dynamic modifications that play a crucial role in various stages of  atherosclerotic plaque progression. Transgenerational transmission of epigenetic modifications increases cardiovascular disease risk, even in offspring. Inflammation within blood vessel walls is linked to lipid metabolism and is crucial for atherosclerosis development. Macrophages and monocytes, when exposed to inflammatory stimuli, undergo alterations in their genetic and epigenetic profiles, thereby contributing to atherosclerosis progression. Our in silico analysis identified HDAC1, HDAC9, HDAC3, SIRT1, and HDAC6 as key hub genes within a protein-protein interaction network of atherosclerosis-related genes.
Conclusion: Understanding epigenetic regulation can provide insights into gene activation related to functions such as inflammation, lipid metabolism, and vascular remodeling, thus influencing atherosclerosis progression. Considering both genetic and epigenetic mechanisms can provide insight into the molecular processes driving atherosclerosis and inform the development of new therapeutic strategies.

Keywords


  1. Su C, Lu Y, Wang Z, Guo J, Hou Y, Wang X, et al. Atherosclerosis: The involvement of immunity, cytokines and cells in pathogenesis, and potential novel therapeutics. Aging and Disease. 2023 Aug 1;14(4):1214.
  2. Fularski P, Czarnik W, Dąbek B, Lisińska W, Radzioch E, Witkowska A, et al. Broader Perspective on Atherosclerosis—Selected Risk Factors, Biomarkers, and Therapeutic Approach. International Journal of Molecular Sciences. 2024 May 10;25(10):5212.
  3. Jebari-Benslaiman S, Galicia-García U, Larrea-Sebal A, Olaetxea JR, Alloza I, Vandenbroeck K, et al. Pathophysiology of atherosclerosis. International journal of molecular sciences. 2022 Mar 20;23(6):3346.
  4. Wentzel JJ. The role of shear stress in atherosclerotic plaque progression, destabilization and rupture. Molecular & Cellular Biomechanics. 2019;16:7.
  5. Huang J, Liang J, Huang L, Li T. Mechanisms of Atherosclerotic Plaque Instability. International Journal of Biology and Life Sciences. 2024 Feb 5(1): 9-12.
  6. Hinkley H, Counts DA, VonCanon E, Lacy M. T cells in atherosclerosis: key players in the pathogenesis of vascular disease. Cells. 2023 Aug 26;12(17):2152.
  7. Jiang H, Zhou Y, Nabavi SM, Sahebkar A, Little PJ, Xu S, et al. Mechanisms of oxidized LDL-mediated endothelial dysfunction and its consequences for the development of atherosclerosis. Frontiers in cardiovascular medicine. 2022 Jun 1;9:925923.medicine/articles/10.3389/fcvm.2022.925923.
  8. Cacciapuoti F. Hyperhomocysteinemia acts via DNA-hypomethylation to induce atherosclerosis. Journal of Cardiology & Current Research.2023 16(2): 38-41.
  9. Chen Y, Liang L, Wu C, Cao Z, Xia L, Meng J, et al. Epigenetic control of vascular smooth muscle cell function in atherosclerosis: a role for DNA methylation. DNA and Cell Biology. 2022 Sep 1;41(9):824-37.
  10. Zima L, West R, Smolen P, Kobori N, Hergenroeder G, Choi HA, et al. Epigenetic modifications and their potential contribution to traumatic brain injury pathobiology and outcome. Journal of Neurotrauma. 2022 Oct 1;39(19-20):1279-88.
  11. Ma C, Seong H, Liu Y, Yu X, Xu S, Li Y. Ten-eleven translocation proteins (TETs): tumor suppressors or tumor enhancers?. Frontiers in Bioscience-Landmark. 2021 Oct 30;26(10):895-915.
  12. Bhat KP, Ümit Kaniskan H, Jin J, Gozani O. Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease. Nature Reviews Drug Discovery. 2021 Apr;20(4):265-86.
  13. Gorabi AM, Penson PE, Banach M, Motallebnezhad M, Jamialahmadi T, Sahebkar A. Epigenetic control of atherosclerosis via DNA methylation: A new therapeutic target?. Life Sciences. 2020 Jul 15;253:117682.
  14. Bonfiglio CA, Lacy M, Janjic A, Avcilar Kucukgoze I, Nitz K, Wu Y, et al. The role of EZH2 and H3K27me3 epigenetic signature in modulating T-cell polarization in atherosclerosis. European Heart Journal. 2023 Nov;44(Supplement_2):ehad655-3232.
  15. Wei X, Zhang Y, Xie L, Wang K, Wang X. Pharmacological inhibition of EZH2 by GSK126 decreases atherosclerosis by modulating foam cell formation and monocyte adhesion in apolipoprotein E-deficient mice. Experimental and Therapeutic Medicine. 2021 Aug;22(2):841.
  16. Eshghjoo S, Kim DM, Jayaraman A, Sun Y, Alaniz RC. Macrophage polarization in atherosclerosis. Genes. 2022 Apr 25;13(5):756.
  17. Hwang JW, Cho Y, Bae GU, Kim SN, Kim YK. Protein arginine methyltransferases: promising targets for cancer therapy. Experimental & molecular medicine. 2021 May;53(5):788-808.
  18. Wang TS, Cheng JK, Lei QY, Wang YP. A switch for transcriptional activation and repression: histone arginine methylation. The DNA, RNA, and Histone Methylomes. 2019:521-41.
  19. Kalani L, Kim BH, Vincent JB, Ausió J. MeCP2 ubiquitination and sumoylation, in search of a function. Human Molecular Genetics. 2024 Jan 1;33(1):1-1.
  20. Pires SF, de Barros JS, da Costa SS, de Oliveira Scliar M, Van Helvoort Lengert A, Boldrini É, et al. DNA methylation patterns suggest the involvement of DNMT3B and TET1 in osteosarcoma development. Molecular Genetics and Genomics. 2023 May;298(3):721-33.
  21. Xie YL, Qin YC, Li AH, Yan ZQ, Qiao ZD, Shanghai Jiaotong University. TET2 modulates proliferation and migration of vascular smooth muscle cells via LEMD2/NOX1/NOX4 signaling pathway. European Heart Journal. 2021 Oct 1;42(Supplement_1):ehab724-3358.
  22. Vasishta S, Ameen B, Adiga P, Umakanth S, Satyamoorthy K, Joshi M. Interplay between DNA methylation and metabolism: Implications in pathogenesis of vascular diseases. Atherosclerosis. 2023 Aug 1;379:S7.
  23. Santoyo-Suarez MG, Mares-Montemayor JD, Padilla-Rivas GR, Delgado-Gallegos JL, Quiroz-Reyes AG, Roacho-Perez JA, et al. The involvement of Krüppel-like factors in cardiovascular diseases. Life. 2023 Feb 2;13(2):420.
  24. Choi HY, Choi S, Iatan I, Ruel I, Genest J. Biomedical advances in ABCA1 transporter: from bench to bedside. Biomedicines. 2023 Feb 15;11(2):561.
  25. Connelly JJ, Cherepanova OA, Doss JF, Karaoli T, Lillard TS, Markunas CA, et al. Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis. Human molecular genetics. 2013 Dec 20;22(25):5107-20.
  26. Dehingia B, Milewska M, Janowski M, Pękowska A. CTCF shapes chromatin structure and gene expression in health and disease. EMBO reports. 2022 Sep 5;23(9):e55146.
  27. Sigala F, Savvari P, Liontos M, Sigalas P, Pateras IS, Papalampros A, et al. Increased expression of bFGF is associated with carotid atherosclerotic plaques instability engaging the NF‐κB pathway. Journal of cellular and molecular medicine. 2010 Sep;14(9):2273-80.
  28. Dai Y, Chen D, Xu T. DNA methylation aberrant in atherosclerosis. Frontiers in Pharmacology. 2022 Mar 3;13:815977.
  29. Lee S, Bartlett B, Dwivedi G. Adaptive immune responses in human atherosclerosis. International journal of molecular sciences. 2020 Dec 7;21(23):9322.
  30. Marques R, Carias E, Domingos A, Guedes A, Bernardo I, Neves P. Prognostic value of lymphocyte cell ratios in peritoneal dialysis. Port J Nephrol Hypert. 2021 Mar;35(1):18-21.
  31. Chen X, Deng C, Wang H, Tang X. Acylations in cardiovascular diseases: advances and perspectives. Chinese Medical Journal. 2022 Jul 5;135(13):1525-7.
  32. Jiang LP, Yu XH, Chen JZ, Hu M, Zhang YK, Lin HL, et al. Histone deacetylase 3: a potential therapeutic target for atherosclerosis. Aging and disease. 2022 Jun 1;13(3):773.
  33. Fol M, Rusek P, Druszczynska M, Wala M. Infectious Agents as Stimuli of Trained Innate Immunity.
  34. Qi L. Nutrition, Genetics, and Cardiovascular Disease. Current Nutrition Reports. 2012 Jun;1:93-9.
  35. Harmancıoğlu B, Kabaran S. Maternal high fat diets: Impacts on offspring obesity and epigenetic hypothalamic programming. Frontiers in genetics. 2023 May 11;14:1158089.
  36. Khajebishak Y, Alivand M, Faghfouri AH, Moludi J, Payahoo L. The effects of vitamins and dietary pattern on epigenetic modification of non-communicable diseases. International Journal for Vitamin and Nutrition Research. 2021 Oct 13.
  37. Wilkinson MJ, Lepor NE, Michos ED. Evolving Management of Low‐Density Lipoprotein Cholesterol: A Personalized Approach to Preventing Atherosclerotic Cardiovascular Disease Across the Risk Continuum. Journal of the American Heart Association. 2023 Jun 6;12(11):e028892.
  38. Bontempo P, Capasso L, De Masi L, Nebbioso A, Rigano D. Therapeutic potential of natural compounds acting through epigenetic mechanisms in cardiovascular diseases: Current findings and future directions. Nutrients. 2024 Jul 24;16(15):2399.
  39. Cao Q, Wang X, Jia L, Mondal AK, Diallo A, Hawkins GA, et al. Inhibiting DNA methylation by 5-Aza-2′-deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation. Endocrinology. 2014 Dec 1;155(12):4925-38.
  40. Brabson JP, Leesang T, Mohammad S, Cimmino L. Epigenetic regulation of genomic stability by vitamin C. Frontiers in genetics. 2021 May 4;12:675780.
  41. Poznyak AV, Wu WK, Melnichenko AA, Wetzker R, Sukhorukov V, Markin AM, et al. Signaling pathways and key genes involved in regulation of foam cell formation in atherosclerosis. Cells. 2020 Mar 1;9(3):584.
  42. Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014 Feb 20;40(2):274-88.