{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:02:21Z","timestamp":1791388941518,"version":"4.3.3"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T00:00:00Z","timestamp":1744329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Thoracic aortic disease (TAD) encompasses a spectrum of life-threatening conditions, including thoracic aortic aneurysm (TAA), acute type A aortic dissection (ATAAD), and bicuspid aortic valve (BAV)-associated aortopathy. While genetic mutations are well-documented contributors, emerging evidence highlights epigenetic mechanisms as critical regulators of TAD pathogenesis. This comprehensive review explores the role of epigenetic modifications\u2014DNA methylation, histone modifications, and microRNA (miRNA) regulation\u2014in vascular remodeling, extracellular matrix degradation, and endothelial dysfunction. Aberrant DNA methylation patterns have been implicated in TAA and ATAAD, influencing genes responsible for vascular integrity and inflammation. Histone modifications modulate smooth muscle cell phenotype switching, impacting aneurysm progression. Additionally, dysregulated miRNA expression contributes to endothelial barrier disruption and extracellular matrix remodeling, presenting novel avenues for biomarker discovery. The reversibility of epigenetic modifications offers a promising therapeutic target, with pharmacological agents such as histone deacetylase inhibitors and miRNA-based therapies showing potential in preclinical models. This review underscores the translational potential of epigenetic biomarkers for early disease detection, risk stratification, and precision medicine approaches. Further research is needed to integrate these findings into clinical practice, paving the way for innovative diagnostic and therapeutic strategies in TAD management.<\/jats:p>","DOI":"10.3390\/biom15040568","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T10:05:51Z","timestamp":1744365951000},"page":"568","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Epigenetic Biomarkers in Thoracic Aortic Aneurysm, Dissection, and Bicuspid Aortopathy: A Comprehensive Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5417-6392","authenticated-orcid":false,"given":"Dimitrios E.","family":"Magouliotis","sequence":"first","affiliation":[{"name":"Department of Cardiac Surgery Research, Lankenau Institute for Medical Research, Main Line Health, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1822-768X","authenticated-orcid":false,"given":"Serge","family":"Sicouri","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery Research, Lankenau Institute for Medical Research, Main Line Health, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah","family":"Sicouri","sequence":"additional","affiliation":[{"name":"Lankenau Medical Center, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3754-6704","authenticated-orcid":false,"given":"Massimo","family":"Baudo","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery Research, Lankenau Institute for Medical Research, Main Line Health, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Cabrucci","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery Research, Lankenau Institute for Medical Research, Main Line Health, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery Research, Lankenau Institute for Medical Research, Main Line Health, Wynnewood, PA 19096, USA"},{"name":"Lankenau Medical Center, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basel","family":"Ramlawi","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery Research, Lankenau Institute for Medical Research, Main Line Health, Wynnewood, PA 19096, USA"},{"name":"Lankenau Medical Center, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rosendorff, C. (2005). Diseases of the Aorta. Essential Cardiology, Humana Press.","DOI":"10.1007\/978-1-59259-918-9"},{"key":"ref_2","first-page":"578","article-title":"Insights from the international registry of acute aortic dissection","volume":"122","author":"Evangelista","year":"2018","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"615175","DOI":"10.3389\/fphys.2021.615175","article-title":"Aortic Dilatation in Patients With Bicuspid Aortic Valve","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_4","first-page":"523","article-title":"Genetics of thoracic aortic aneurysm","volume":"74","author":"Pinard","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kim,  H.W., Stansfield, B.K., and Zabirnyk, A. (2017). Genetic and Epigenetic Regulation of Aortic Aneurysms. Biomed. Res. Int.  , 2017.","DOI":"10.1155\/2017\/7268521"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1161\/CIRCULATIONAHA.123.063332","article-title":"Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections","volume":"148","author":"Chakraborty","year":"2023","journal-title":"Circulation"},{"key":"ref_7","first-page":"1784","article-title":"Genetics of thoracic aortic aneurysm: At the crossroad of transforming growth factor-\u03b2 signaling and vascular smooth muscle cell contractility","volume":"120","author":"Gillis","year":"2017","journal-title":"Circ. Res."},{"key":"ref_8","first-page":"101","article-title":"Epigenetic regulation of vascular smooth muscle cell function in thoracic aortic aneurysm","volume":"133","author":"Shen","year":"2019","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_9","first-page":"168","article-title":"The role of histone deacetylase inhibitors in thoracic aortic aneurysm and dissection: A potential therapeutic strategy?","volume":"306","author":"Phan","year":"2020","journal-title":"Int. J. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1055\/s-0038-1639610","article-title":"Epigenetics in Ascending Thoracic Aortic Aneurysm and Dissection","volume":"6","author":"Boileau","year":"2018","journal-title":"Aorta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"122ra22","DOI":"10.1126\/scitranslmed.3003441","article-title":"MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion","volume":"4","author":"Maegdefessel","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chen, Y., Xu, X., Chen, Z., Huang, B., Wang, X., and Fan, X. (2022). DNA methylation alternation in Stanford\u2014A acute aortic dissection. BMC Cardiovasc. Disord., 22.","DOI":"10.1186\/s12872-022-02882-5"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1007\/s12551-018-0460-1","article-title":"Epigenetic influences on genetically triggered thoracic aortic aneurysm","volume":"10","author":"Portelli","year":"2018","journal-title":"Biophys. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1161\/ATVBAHA.119.312193","article-title":"Epigenetic Regulation of Vascular Diseases","volume":"39","author":"Zarzour","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Moushi, A., Pillar, N., Keravnou, A., Soteriou, M., Shomron, N., Cariolou, M.A., and Bashiardes, E. (2020). MicroRNAs in ascending thoracic aortic aneurysms. Biosci. Rep., 40.","DOI":"10.1042\/BSR20200218"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41392-022-01055-2","article-title":"Epigenetic regulation in cardiovascular disease: Mechanisms and advances in clinical trials","volume":"7","author":"Shi","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e002317","DOI":"10.1136\/openhrt-2023-002317","article-title":"Circulating biomarkers associated with aortic diameter in male and female patients with thoracic aortic disease: A cross-sectional study","volume":"10","author":"Meccanici","year":"2023","journal-title":"Open Heart"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1093\/cvr\/cvx050","article-title":"DNA methylome analysis reveals distinct epigenetic patterns of ascending aortic dissection and bicuspid aortic valve","volume":"113","author":"Pan","year":"2017","journal-title":"Cardiovasc. Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Atkinson, G., Bianco, R., Di Gregoli, K., and Johnson, J.L. (2023). The contribution of matrix metalloproteinases and their inhibitors to the development, progression, and rupture of abdominal aortic aneurysms. Front. Cardiovasc. Med., 10.","DOI":"10.3389\/fcvm.2023.1248561"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Takeda, N., Hara, H., Fujiwara, T., Kanaya, T., Maemura, S., and Komuro, I. (2018). TGF-\u03b2 Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19072125"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1093\/cvr\/cvs352","article-title":"SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence","volume":"97","author":"Cardus","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13148-021-01110-9","article-title":"Altered DNA methylation pattern reveals epigenetic regulation of Hox genes in thoracic aortic dissection and serves as a biomarker in disease diagnosis","volume":"13","author":"Liu","year":"2021","journal-title":"Clin. Egenetics"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Forrer, A., Schoenrath, F., Torzewski, M., Schmid, J., Franke, U.F.W., G\u00f6bel, N., Aujesky, D., Matter, C.M., L\u00fcscher, T.F., and Mach, F. (2021). Novel Blood Biomarkers for a Diagnostic Workup of Acute Aortic Dissection. Diagnostics, 11.","DOI":"10.3390\/diagnostics11040615"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Magouliotis, D.E., Sicouri, S., Rad, A.A., Skoularigis, J., Giamouzis, G., Xanthopoulos, A., Karamolegkou, A.P., Viviano, A., Athanasiou, T., and Ramlawi, B. (2025). In-depth computational analysis reveals the significant dysregulation of key gap junction proteins (GJPs) driving thoracic aortic aneurysm development. Hell. J. Cardiol., Epub ahead of print.","DOI":"10.1016\/j.hjc.2025.01.001"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Magouliotis, D.E., Arjomandi Rad, A., Kourliouros, A., Viviano, A., Koulouroudias, M., Salmasi, M.Y., Briasoulis, A., Triposkiadis, F., Skoularigis, J., and Athanasiou, T. (2023). Transcriptomic Analysis of Tight Junction Proteins Demonstrates the Aberrant Expression and Function of Zona Occludens 2 (ZO-2) Protein in Stanford Type A Aortic Dissection. J. Pers. Med., 13.","DOI":"10.3390\/jpm13121697"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1093\/eurheartj\/ehac823","article-title":"Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection","volume":"44","author":"Yang","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e124706","DOI":"10.1172\/jci.insight.124706","article-title":"HDAC9 complex inhibition improves smooth muscle-dependent stenotic vascular disease","volume":"4","author":"Kessinger","year":"2019","journal-title":"JCI Insight"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gurung, R., Choong, A.M., Woo, C.C., Foo, R., and Sorokin, V. (2020). Genetic and Epigenetic Mechanisms Underlying Vascular Smooth Muscle Cell Phenotypic Modulation in Abdominal Aortic Aneurysm. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176334"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1111\/bph.16409","article-title":"Non-coding RNAs to treat vascular smooth muscle cell dysfunction","volume":"182","author":"Brown","year":"2025","journal-title":"Br. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.yjmcc.2013.05.009","article-title":"MicroRNA-25-dependent up-regulation of NADPH oxidase 4 (NOX4) mediates hypercholesterolemia-induced oxidative\/nitrative stress and subsequent dysfunction in the heart","volume":"62","author":"Varga","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1186\/s12964-024-01803-7","article-title":"The role of miR-155-5p in inflammation and mechanical loading during intervertebral disc degeneration","volume":"22","author":"Cazzanelli","year":"2024","journal-title":"Cell Commun. Signal."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41419-020-2645-3","article-title":"LncRNA ANRIL acts as a modular scaffold of WDR5 and HDAC3 complexes and promotes alteration of the vascular smooth muscle cell phenotype","volume":"11","author":"Zhang","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_33","first-page":"1474","article-title":"Challenges in the analysis of epigenetic biomarkers in clinical samples","volume":"55","year":"2017","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1093\/ejcts\/ezab338","article-title":"In-depth bioinformatic study of the cadherin 5 interactome in patients with thoracic aortic aneurysm unveils 8 novel biomarkers","volume":"61","author":"Magouliotis","year":"2021","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41392-024-02039-0","article-title":"Epigenetics-targeted drugs: Current paradigms and future challenges","volume":"9","author":"Dai","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Bell, C.G., Lowe, R., Adams, P.D., Baccarelli, A.A., Beck, S., Bell, J.T., Christensen, B.C., Gladyshev, V.N., Heijmans, B.T., and Horvath, S. (2019). DNA methylation aging clocks: Challenges and recommendations. Genome Biol., 20.","DOI":"10.1186\/s13059-019-1824-y"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"376","DOI":"10.3322\/caac.21765","article-title":"Cancer epigenetics in clinical practice","volume":"73","author":"Davalos","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Moore-Smith, L.D., Isayeva, T., Lee, J.H., Frost, A., and Ponnazhagan, S. (2017). Silencing of TGF-\u03b21 in tumor cells impacts MMP-9 in tumor microenvironment. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-09062-y"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/nrg2562","article-title":"Ethical implications of epigenetics research","volume":"10","author":"Rothstein","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"923","DOI":"10.3892\/ijmm.2014.1853","article-title":"MicroRNAs regulate vascular smooth muscle cell functions in atherosclerosis (review)","volume":"34","author":"Yu","year":"2014","journal-title":"Int. J. Mol. Med."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/4\/568\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:12:51Z","timestamp":1760029971000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/4\/568"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,11]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["biom15040568"],"URL":"https:\/\/doi.org\/10.3390\/biom15040568","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,11]]}}}