Histone Modifications in Cardiovascular Disease: Mechanisms and Therapeutic Opportunities

Abstract

Cardiovascular diseases remain the leading cause of death worldwide. Maladaptive transcriptional programs drive the fibrosis, hypertrophy, and vascular inflammation that characterize these pathologies. Histone posttranslational modifications regulate these programs by remodeling chromatin accessibility and transcriptional output in cardiomyocytes, vascular cells, and immune cells. These modifications include methylation, acetylation, and metabolite-derived acylations. While the enzymatic machinery of classical histone marks is increasingly well defined, the cell-type-specific integration of these regulators into dynamic cardiovascular networks remains incompletely understood. This narrative review summarizes experimental and human studies published up to early 2026. We examine how classical marks such as H3K27me3 and H3K9ac, alongside emerging metabolic sensors like histone lysine lactylation, shape core pathobiological programs, including oxidative stress responses, endothelial dysfunction, and extracellular matrix remodeling, across major cardiovascular syndromes. We further critically evaluate the enzymatic machinery and pharmacological strategies by contrasting broad-spectrum histone deacetylase inhibition with precision approaches, including bromodomain inhibition and locus-selective epigenome editing. Finally, we address translational constraints such as drug delivery and off-target effects. We propose that single-cell resolution and spatial multiomics will be essential to identify compartment-specific targets and advance precision cardiovascular epigenetic therapeutics.

Keywords

atherosclerosis / heart failure / histone posttranslational modifications / hypertension / myocardial infarction / myocardial ischemia–reperfusion injury

References

[1] Global Burden of Cardiovascular Diseases and Risks 2023 Collaborators, “Global, Regional, and National Burden of Cardiovascular Diseases and Risk Factors in 204 Countries and Territories, 1990–2023,” Journal of the American College of Cardiology 86 (2025): 2167–2243.

[2] G. Heusch, “Myocardial Ischaemia-reperfusion Injury and Cardioprotection in Perspective,” Nature Reviews Cardiology 17 (2020): 773–789.

[3] F. G. P. Welt, W. Batchelor, J. R. Spears, et al., “Reperfusion Injury in Patients with Acute Myocardial Infarction: JACC Scientific Statement,” Journal of the American College of Cardiology 83 (2024): 2196–2213.

[4] J. M. Lorenzen, F. Martino, and T. Thum, “Epigenetic Modifications in Cardiovascular Disease,” Basic Research in Cardiology 107 (2012): 245.

[5] Y. Shi, H. Zhang, S. Huang, et al., “Epigenetic Regulation in Cardiovascular Disease: Mechanisms and Advances in Clinical Trials,” Signal Transduction and Targeted Therapy 7 (2022): 200.

[6] A. J. Bannister and T. Kouzarides, “Regulation of Chromatin by Histone Modifications,” Cell Research 21 (2011): 381–395.

[7] D. Zhang, Z. Tang, H. Huang, et al., “Metabolic Regulation of Gene Expression by Histone Lactylation,” Nature 574 (2019): 575–580.

[8] P. Anand, J. D. Brown, C. Y. Lin, et al., “BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure,” Cell 154 (2013): 569–582.

[9] K. Kalantar-Zadeh, G. G. Schwartz, S. J. Nicholls, et al., “Effect of Apabetalone on Cardiovascular Events in Diabetes, CKD, and Recent Acute Coronary Syndrome: Results From the BETonMACE Randomized Controlled Trial,” Clinical Journal of the American Society of Nephrology 16 (2021): 705–716.

[10] B. R. Zhou and Y. Bai, “Chromatin Structures Condensed by Linker Histones,” Essays in Biochemistry 63 (2019): 75–87.

[11] R. M. W. Colpaert and M. Calore, “Epigenetics and microRNAs in Cardiovascular Diseases,” Genomics 113 (2021): 540–551.

[12] M. Shirvaliloo, “The Landscape of Histone Modifications in Epigenomics Since 2020,” Epigenomics 14 (2022): 1465–1477.

[13] K. J. Wu, Q. Chen, C. H. Leung, N. Sun, F. Gao, and Z. Chen, “Recent Discoveries of the Role of Histone Modifications and Related Inhibitors in Pathological Cardiac Hypertrophy,” Drug Discovery Today 29 (2024): 103878.

[14] Y. Z. Kim, “Altered Histone Modifications in Gliomas,” Brain Tumor Research and Treatment 2 (2014): 7–21.

[15] D. J. Marsh, J. S. Shah, and A. J. Cole, “Histones and Their Modifications in Ovarian Cancer—drivers of Disease and Therapeutic Targets,” Frontiers in Oncology 4 (2014): 144.

[16] M. S. Stratton, R. A. Bagchi, M. B. Felisbino, et al., “Dynamic Chromatin Targeting of BRD4 Stimulates Cardiac Fibroblast Activation,” Circulation Research 125 (2019): 662–677.

[17] Y. Yang, Y. Luan, R. X. Yuan, and Y. Luan, “Histone Methylation Related Therapeutic Challenge in Cardiovascular Diseases,” Frontiers in Cardiovascular Medicine 8 (2021): 710053.

[18] Q. Jun, L. Youhong, Z. Yuan, et al., “Histone Modification of Endothelial-mesenchymal Transition in Cardiovascular Diseases,” Frontiers in Cardiovascular Medicine 9 (2022): 1022988.

[19] B. M. Lorton, R. K. Harijan, E. S. Burgos, J. B. Bonanno, S. C. Almo, and D. Shechter, “A Binary Arginine Methylation Switch on Histone H3 Arginine 2 Regulates Its Interaction With WDR5,” Biochemistry 59 (2020): 3696–3708.

[20] Y. Song, S. Wang, and B. Yu, “Structural and Functional Landscape of FAD-Dependent Histone Lysine Demethylases for New Drug Discovery,” Journal of Medicinal Chemistry 66 (2023): 71–94.

[21] M. Shvedunova and A. Akhtar, “Modulation of Cellular Processes by Histone and Non-histone Protein Acetylation,” Nature Reviews Molecular Cell Biology 23 (2022): 329–349.

[22] S. Y. Roth, J. M. Denu, and C. D. Allis, “Histone Acetyltransferases,” Annual Review of Biochemistry 70 (2001): 81–120.

[23] E. Seto and M. Yoshida, “Erasers of Histone Acetylation: The Histone Deacetylase Enzymes,” Cold Spring Harbor Perspectives in Biology 6 (2014): a018713.

[24] J. Li, B. Mahata, M. Escobar, et al., “Programmable human Histone Phosphorylation and Gene Activation Using a CRISPR/Cas9-based Chromatin Kinase,” Nature Communications 12 (2021): 896.

[25] P. Gong, Z. Guo, S. Wang, S. Gao, and Q. Cao, “Histone Phosphorylation in DNA Damage Response,” International Journal of Molecular Sciences 26 (2025): 2405.

[26] D. Rossetto, N. Avvakumov, and J. Côté, “Histone Phosphorylation: A Chromatin Modification Involved in Diverse Nuclear Events,” Epigenetics 7 (2012): 1098–1108.

[27] E. P. Rogakou, D. R. Pilch, A. H. Orr, V. S. Ivanova, and W. M. Bonner, “DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139,” Journal of Biological Chemistry 273 (1998): 5858–5868.

[28] S. Nakada, G. I. Chen, A. C. Gingras, and D. Durocher, “PP4 is a Gamma H2AX Phosphatase Required for Recovery From the DNA Damage Checkpoint,” Embo Reports 9 (2008): 1019–1026.

[29] M. Stucki, J. A. Clapperton, D. Mohammad, M. B. Yaffe, S. J. Smerdon, and S. P. Jackson, “MDC1 directly Binds Phosphorylated Histone H2AX to Regulate Cellular Responses to DNA Double-strand Breaks,” Cell 123 (2005): 1213–1226.

[30] A. Sawicka and C. Seiser, “Sensing Core Histone Phosphorylation—a Matter of Perfect Timing,” Biochimica Et Biophysica Acta 1839 (2014): 711–718.

[31] D. Huang, C. V. Camacho, R. Setlem, et al., “Functional Interplay Between Histone H2B ADP-Ribosylation and Phosphorylation Controls Adipogenesis,” Molecular Cell 79 (2020): 934–949 e14.

[32] A. Saha, C. H. Seward, L. Stubbs, and C. A. Mizzen, “Site-Specific Phosphorylation of Histone H1.4 Is Associated With Transcription Activation,” International Journal of Molecular Sciences 21 (2020): 8861.

[33] M. Sekiguchi and N. Matsushita, “DNA Damage Response Regulation by Histone Ubiquitination,” International Journal of Molecular Sciences 23 (2022): 8187.

[34] R. Meas and P. Mao, “Histone Ubiquitylation and Its Roles in Transcription and DNA Damage Response,” DNA Repair 36 (2015): 36–42.

[35] S. Manohar, S. Jacob, J. Wang, et al., “Polyubiquitin Chains Linked by Lysine Residue 48 (K48) Selectively Target Oxidized Proteins in Vivo,” Antioxid Redox Signaling 31 (2019): 1133–1149.

[36] M. Tan, H. Luo, S. Lee, et al., “Identification of 67 Histone Marks and Histone Lysine Crotonylation as a New Type of Histone Modification,” Cell 146 (2011): 1016–1028.

[37] B. R. Sabari, Z. Tang, H. Huang, et al., “Intracellular Crotonyl-CoA Stimulates Transcription Through p300-catalyzed Histone Crotonylation,” Molecular Cell 58 (2015): 203–215.

[38] Y. Li, B. R. Sabari, T. Panchenko, et al., “Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain,” Molecular Cell 62 (2016): 181–193.

[39] E. Montellier, S. Rousseaux, Y. Zhao, and S. Khochbin, “Histone Crotonylation Specifically Marks the Haploid Male Germ Cell Gene Expression Program: Post-meiotic Male-specific Gene Expression,” BioEssays 34 (2012): 187–193.

[40] O. Ruiz-Andres, M. D. Sanchez-Niño, P. Cannata-Ortiz, et al., “Histone Lysine Crotonylation During Acute Kidney Injury in Mice,” Disease Models & Mechanisms 9 (2016): 633–645.

[41] J. Wan, H. Liu, and L. Ming, “Lysine Crotonylation Is Involved in Hepatocellular Carcinoma Progression,” Biomedicine & Pharmacotherapy 111 (2019): 976–982.

[42] G. Jiang, D. Nguyen, N. M. Archin, et al., “HIV Latency Is Reversed by ACSS2-driven Histone Crotonylation,” Journal of Clinical Investigation 128 (2018): 1190–1198.

[43] Z. Wang, K. Li, X. Wang, and W. Huang, “MiR-155-5p Modulates HSV-1 Replication via the Epigenetic Regulation of SRSF2 Gene Expression,” Epigenetics 14 (2019): 494–503.

[44] W. Cai, D. Xu, C. Zeng, et al., “Modulating Lysine Crotonylation in Cardiomyocytes Improves Myocardial Outcomes,” Circulation Research 131 (2022): 456–472.

[45] K. Arita, H. Hashimoto, T. Shimizu, K. Nakashima, M. Yamada, and M. Sato, “Structural basis for Ca(+)-induced Activation of human PAD4,” Nature Structural & Molecular Biology 11 (2004): 777–783.

[46] X. Zhang, G. Xie, L. Rao, and C. Tian, “Citrullination in Health and Disease: From Physiological Function to Gene Regulation,” Genes & Diseases 12 (2025): 101355.

[47] Y. Wang, J. Wysocka, J. Sayegh, et al., “Human PAD4 Regulates Histone Arginine Methylation Levels via Demethylimination,” Science 306 (2004): 279–283.

[48] K. W. Clancy, A. M. Russell, V. Subramanian, et al., “Citrullination/Methylation Crosstalk on Histone H3 Regulates ER-Target Gene Transcription,” ACS Chemical Biology 12 (2017): 1691–1702.

[49] X. Zhang, X. Liu, M. Zhang, et al., “Peptidylarginine Deiminase 1-catalyzed Histone Citrullination Is Essential for Early Embryo Development,” Scientific Reports 6 (2016): 38727.

[50] D. Zhu, Y. Zhang, and S. Wang, “Histone Citrullination: A New Target for Tumors,” Molecular Cancer 20 (2021): 90.

[51] N. Golenberg, J. M. Squirrell, D. A. Bennin, et al., “Citrullination Regulates Wound Responses and Tissue Regeneration in Zebrafish,” Journal of Cell Biology 219 (2020): e201908164.

[52] S. Tohme, H. O. Yazdani, A. B. Al-Khafaji, et al., “Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases After Surgical Stress,” Cancer Research 76 (2016): 1367–1380.

[53] L. Zhang, C. Xia, Y. Yang, et al., “DNA Methylation and Histone Post-translational Modifications in Atherosclerosis and a Novel Perspective for Epigenetic Therapy,” Cell Communication and Signaling 21 (2023): 344.

[54] Y. Lin, T. Qiu, G. Wei, et al., “Role of Histone Post-Translational Modifications in Inflammatory Diseases,” Frontiers in Immunology 13 (2022): 852272.

[55] J. S. Knight, W. Luo, A. A. O'Dell, et al., “Peptidylarginine Deiminase Inhibition Reduces Vascular Damage and Modulates Innate Immune Responses in Murine Models of Atherosclerosis,” Circulation Research 114 (2014): 947–956.

[56] Y. Döring, O. Soehnlein, and C. Weber, “Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis,” Circulation Research 120 (2017): 736–743.

[57] B. P. Ashburner, S. D. Westerheide, and A. S. Baldwin, “The p65 (RelA) Subunit of NF-kappaB Interacts With the Histone Deacetylase (HDAC) Corepressors HDAC1 and HDAC2 to Negatively Regulate Gene Expression,” Molecular and Cellular Biology 21 (2001): 7065–7077.

[58] Z. L. Yuan, Y. J. Guan, D. Chatterjee, and Y. E. Chin, “Stat3 dimerization Regulated by Reversible Acetylation of a Single Lysine Residue,” Science 307 (2005): 269–273.

[59] Z. Chi, S. Chen, T. Xu, et al., “Histone Deacetylase 3 Couples Mitochondria to Drive IL-1β-Dependent Inflammation by Configuring Fatty Acid Oxidation,” Molecular Cell 80 (2020): 43–58 e7.

[60] K. Inoue, M. Kobayashi, K. Yano, et al., “Histone Deacetylase Inhibitor Reduces Monocyte Adhesion to Endothelium Through the Suppression of Vascular Cell Adhesion Molecule-1 Expression,” Arteriosclerosis, Thrombosis, and Vascular Biology 26 (2006): 2652–2659.

[61] A. Zampetaki, L. Zeng, A. Margariti, et al., “Histone Deacetylase 3 Is Critical in Endothelial Survival and Atherosclerosis Development in Response to Disturbed Flow,” Circulation 121 (2010): 132–142.

[62] M. A. Hoeksema, M. J. Gijbels, J. Van den Bossche, et al., “Targeting Macrophage Histone Deacetylase 3 Stabilizes Atherosclerotic Lesions,” EMBO Molecular Medicine 6 (2014): 1124–1132.

[63] T. Usui, M. Okada, W. Mizuno, et al., “HDAC4 mediates Development of Hypertension via Vascular Inflammation in Spontaneous Hypertensive Rats,” American Journal of Physiology. Heart and Circulatory Physiology 302 (2012): H1894–H1904.

[64] K. D. Gupta, M. R. Shakespear, J. E. B. Curson, et al., “Class IIa Histone Deacetylases Drive Toll-Like Receptor-Inducible Glycolysis and Macrophage Inflammatory Responses via Pyruvate Kinase M2,” Cell Reports 30 (2020): 2712–2728.

[65] J. Zhang, S. M. Lee, S. Shannon, et al., “The Type III Histone Deacetylase Sirt1 Is Essential for Maintenance of T Cell Tolerance in Mice,” Journal of Clinical Investigation 119 (2009): 3048–3058.

[66] Q. Zhou, Y. Wang, Z. Lu, et al., “Mitochondrial Dysfunction Caused by SIRT3 Inhibition Drives Proinflammatory Macrophage Polarization in Obesity,” Obesity (Silver Spring) 31 (2023): 1050–1063.

[67] W. Vanden Berghe, K. De Bosscher, E. Boone, S. Plaisance, and G. Haegeman, “The Nuclear Factor-kappaB Engages CBP/p300 and Histone Acetyltransferase Activity for Transcriptional Activation of the Interleukin-6 Gene Promoter,” Journal of Biological Chemistry 274 (1999): 32091–32098.

[68] W. G. Deng, Y. Zhu, and K. K. Wu, “Role of p300 and PCAF in Regulating Cyclooxygenase-2 Promoter Activation by Inflammatory Mediators,” Blood 103 (2004): 2135–2142.

[69] M. L. Vlad, S. A. Manea, A. G. Lazar, et al., “Histone Acetyltransferase-Dependent Pathways Mediate Upregulation of NADPH Oxidase 5 in Human Macrophages Under Inflammatory Conditions: A Potential Mechanism of Reactive Oxygen Species Overproduction in Atherosclerosis,” Oxidative Medicine and Cellular Longevity 2019 (2019): 3201062.

[70] X. Yu, H. Chen, C. Zuo, et al., “Chromatin Remodeling: Demethylating H3K4me3 of Type I IFNs Gene by Rbp2 Through Interacting With Piasy for Transcriptional Attenuation,” Faseb Journal 32 (2018): 552–567.

[71] X. Li, Q. Zhang, Q. Shi, et al., “Demethylase Kdm6a Epigenetically Promotes IL-6 and IFN-β Production in Macrophages,” Journal of Autoimmunity 80 (2017): 85–94.

[72] X. Zhuo, Y. Wu, Y. Yang, L. Gao, X. Qiao, and T. Chen, “Knockdown of LSD1 Meliorates Ox-LDL-stimulated NLRP3 Activation and Inflammation by Promoting Autophagy via SESN2-mesiated PI3K/Akt/mTOR Signaling Pathway,” Life Sciences 233 (2019): 116696.

[73] X. Zhang, J. Sun, A. Canfrán-Duque, et al., “Deficiency of Histone Lysine Methyltransferase SETDB2 in Hematopoietic Cells Promotes Vascular Inflammation and Accelerates Atherosclerosis,” JCI Insight 6 (2021): e147984.

[74] S. A. Manea, M. L. Vlad, A. G. Lazar, H. Muresian, M. Simionescu, and A. Manea, “Pharmacological Inhibition of Lysine-Specific Demethylase 1A Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Deficient Mice by a Mechanism Involving Decreased Oxidative Stress and Inflammation; Potential Implications in Human Atherosclerosis,” Antioxidants (Basel) 11 (2022): 2382.

[75] R. A. Irizarry-Caro, M. M. McDaniel, G. R. Overcast, V. G. Jain, T. D. Troutman, and C. Pasare, “TLR Signaling Adapter BCAP Regulates Inflammatory to Reparatory Macrophage Transition by Promoting Histone Lactylation,” Proceedings of the National Academy of Sciences of the United States of America 117 (2020): 30628–30638.

[76] N. Wang, W. Wang, X. Wang, et al., “Histone Lactylation Boosts Reparative Gene Activation Post-Myocardial Infarction,” Circulation Research 131 (2022): 893–908.

[77] Y. Wang, M. Li, S. Stadler, et al., “Histone Hypercitrullination Mediates Chromatin Decondensation and Neutrophil Extracellular Trap Formation,” Journal of Cell Biology 184 (2009): 205–213.

[78] P. Li, M. Li, M. R. Lindberg, M. J. Kennett, N. Xiong, and Y. Wang, “PAD4 is Essential for Antibacterial Innate Immunity Mediated by Neutrophil Extracellular Traps,” Journal of Experimental Medicine 207 (2010): 1853–1862.

[79] T. Josefs, T. J. Barrett, E. J. Brown, et al., “Neutrophil Extracellular Traps Promote Macrophage Inflammation and Impair Atherosclerosis Resolution in Diabetic Mice,” JCI Insight 5 (2020): e134796.

[80] K. M. Kindberg, K. Broch, G. Andersen, et al., “Neutrophil Extracellular Traps in ST-Segment Elevation Myocardial Infarction: Reduced by Tocilizumab and Associated with Infarct Size,” JACC Advances 3 (2024): 101193.

[81] M. Benkhoff, K. Alde, V. Ehreiser, et al., “Thromboinflammation Is Associated With Clinical Outcome After ST-elevation Myocardial Infarction,” Blood Advances 8 (2024): 5581–5589.

[82] J. Natorska, M. Ząbczyk, and A. Undas, “Neutrophil Extracellular Traps (NETs) in Cardiovascular Diseases: From Molecular Mechanisms to Therapeutic Interventions,” Kardiologia Polska 81 (2023): 1205–1216.

[83] Y. Chen, J. Zhang, Y. Lin, et al., “Tumour Suppressor SIRT3 Deacetylates and Activates Manganese Superoxide Dismutase to Scavenge ROS,” Embo Reports 12 (2011): 534–541.

[84] W. Yu, K. E. Dittenhafer-Reed, and J. M. Denu, “SIRT3 protein Deacetylates Isocitrate Dehydrogenase 2 (IDH2) and Regulates Mitochondrial Redox Status,” Journal of Biological Chemistry 287 (2012): 14078–14086.

[85] N. T. Boardman, B. Migally, C. Pileggi, et al., “Glutaredoxin-2 and Sirtuin-3 Deficiencies Impair Cardiac Mitochondrial Energetics but Their Effects Are Not Additive,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1867 (2021): 165982.

[86] R. R. Alcendor, S. Gao, P. Zhai, et al., “Sirt1 regulates Aging and Resistance to Oxidative Stress in the Heart,” Circulation Research 100 (2007): 1512–1521.

[87] T. Kawashima, Y. Inuzuka, J. Okuda, et al., “Constitutive SIRT1 Overexpression Impairs Mitochondria and Reduces Cardiac Function in Mice,” Journal of Molecular and Cellular Cardiology 51 (2011): 1026–1036.

[88] L. E. Greiten, B. Zhang, C. M. Roos, M. Hagler, F. P. Jahns, and J. D. Miller, “Sirtuin 6 Protects against Oxidative Stress and Vascular Dysfunction in Mice,” Frontiers in Physiology 12 (2021): 753501.

[89] Y. Leng, Y. Wu, S. Lei, et al., “Inhibition of HDAC6 Activity Alleviates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats: Potential Role of Peroxiredoxin 1 Acetylation and Redox Regulation,” Oxidative Medicine and Cellular Longevity 2018 (2018): 9494052.

[90] C. Li, J. Chang, Y. Wang, and G. Pan, “Indole-3-propionic Acid, a Product of Intestinal Flora, Inhibits the HDAC6/NOX2 Signalling and Relieves Doxorubicin-induced Cardiomyocyte Damage,” Folia Morphologiica 83 (2024): 382–390.

[91] Y. Nakagawa, K. Kuwahara, G. Takemura, et al., “p300 plays a Critical Role in Maintaining Cardiac Mitochondrial Function and Cell Survival in Postnatal Hearts,” Circulation Research 105 (2009): 746–754.

[92] S. A. Manea, M. L. Vlad, A. G. Lazar, H. Muresian, M. Simionescu, and A. Manea, “SET7 lysine Methyltransferase Mediates the Up-regulation of NADPH Oxidase Expression, Oxidative Stress, and NLRP3 Inflammasome Priming in Atherosclerosis,” Journal of Translational Medicine 23 (2025): 339.

[93] A. Fei, L. Li, Y. Liu, Z. Lv, and J. Jin, “Histone Demethylase PHF8 Confers Protection Against Oxidative Stress and Cardiomyocyte Apoptosis in Heart Failure by Upregulating FOXA2,” International Heart Journal 66 (2025): 114–125.

[94] X. H. Zhu, J. W. Hou, Z. Y. Lv, et al., “Hypoxia-Induced Histone Lactylation Promotes Ferroptosis in Cardiomyocytes via the Wnt/β-Catenin Pathway,” The Kaohsiung Journal of Medical Sciences 42 (2025): e70123.

[95] W. Yu, Q. Kong, S. Jiang, et al., “HSPA12A maintains Aerobic Glycolytic Homeostasis and Histone3 Lactylation in Cardiomyocytes to Attenuate Myocardial Ischemia/Reperfusion Injury,” JCI Insight 9 (2024): e169125.

[96] J. Chen, M. Zhang, Y. Liu, et al., “Histone Lactylation Driven by mROS-mediated Glycolytic Shift Promotes Hypoxic Pulmonary Hypertension,” Journal of Molecular Cell Biology 14 (2023): mjac073.

[97] J. E. Bishop, R. Greenbaum, D. G. Gibson, M. Yacoub, and G. J. Laurent, “Enhanced Deposition of Predominantly Type I Collagen in Myocardial Disease,” Journal of Molecular and Cellular Cardiology 22 (1990): 1157–1165.

[98] J. P. Cleutjens, M. J. Verluyten, J. F. Smiths, and M. J. Daemen, “Collagen Remodeling After Myocardial Infarction in the Rat Heart,” American Journal of Pathology 147 (1995): 325–338.

[99] J. Shao, J. Liu, and S. Zuo, “Roles of Epigenetics in Cardiac Fibroblast Activation and Fibrosis,” Cells 11 (2022): 2347.

[100] N. Garitano, L. P. Aguado-Alvaro, and B. Pelacho, “Emerging Epigenetic Therapies for the Treatment of Cardiac Fibrosis,” Biomedicines 13 (2025): 1170.

[101] K. O. Leslie, D. J. Taatjes, J. Schwarz, M. vonTurkovich, and R. B. Low, “Cardiac Myofibroblasts Express Alpha Smooth Muscle Actin During Right Ventricular Pressure Overload in the Rabbit,” American Journal of Pathology 139 (1991): 207–216.

[102] V. Fowlkes, J. Clark, C. Fix, et al., “Type II Diabetes Promotes a Myofibroblast Phenotype in Cardiac Fibroblasts,” Life Sciences 92 (2013): 669–676.

[103] A. K. Ghosh, S. Bhattacharyya, J. Wei, et al., “Peroxisome Proliferator-activated Receptor-gamma Abrogates Smad-dependent Collagen Stimulation by Targeting the p300 Transcriptional Coactivator,” Faseb Journal 23 (2009): 2968–2977.

[104] R. Rai, T. Sun, V. Ramirez, et al., “Acetyltransferase p300 Inhibitor Reverses Hypertension-induced Cardiac Fibrosis,” Journal of Cellular and Molecular Medicine 23 (2019): 3026–3031.

[105] T. Morimoto, Y. Sunagawa, T. Kawamura, et al., “The Dietary Compound Curcumin Inhibits p300 Histone Acetyltransferase Activity and Prevents Heart Failure in Rats,” Journal of Clinical Investigation 118 (2008): 868–878.

[106] K. Shimizu, Y. Sunagawa, M. Funamoto, et al., “The Synthetic Curcumin Analogue GO-Y030 Effectively Suppresses the Development of Pressure Overload-induced Heart Failure in Mice,” Scientific Reports 10 (2020): 7172.

[107] B. K. Duvey, D. Sharma, V. Mittal, and A. Sharma, “Role of Perturbations of Epigenetic Processes in Cardiac Hypertrophy and Fibrotic Scarring,” Current Cardiology Reviews 22 (2026): e1573403×354902.

[108] H. F. Nural-Guvener, L. Zakharova, J. Nimlos, S. Popovic, D. Mastroeni, and M. A. Gaballa, “HDAC Class I Inhibitor, Mocetinostat, Reverses Cardiac Fibrosis in Heart Failure and Diminishes CD90+ Cardiac Myofibroblast Activation,” Fibrogenesis Tissue Repair 7 (2014): 10.

[109] L. Yu, G. Yang, X. Weng, et al., “Histone Methyltransferase SET1 Mediates Angiotensin II-Induced Endothelin-1 Transcription and Cardiac Hypertrophy in Mice,” Arteriosclerosis, Thrombosis, and Vascular Biology 35 (2015): 1207–1217.

[110] Q. J. Zhang, T. A. T. Tran, M. Wang, et al., “Histone Lysine Dimethyl-demethylase KDM3A Controls Pathological Cardiac Hypertrophy and Fibrosis,” Nature Communications 9 (2018): 5230.

[111] S. Song, R. Zhang, B. Mo, et al., “EZH2 as a Novel Therapeutic Target for Atrial Fibrosis and Atrial Fibrillation,” Journal of Molecular and Cellular Cardiology 135 (2019): 119–133.

[112] A. B. Gaikwad, S. G. Sayyed, J. Lichtnekert, K. Tikoo, and H. J. Anders, “Renal Failure Increases Cardiac Histone h3 Acetylation, Dimethylation, and Phosphorylation and the Induction of Cardiomyopathy-related Genes in Type 2 Diabetes,” American Journal of Pathology 176 (2010): 1079–1083.

[113] M. Fan, K. Yang, X. Wang, et al., “Lactate Promotes Endothelial-to-mesenchymal Transition via Snail1 Lactylation After Myocardial Infarction,” Science Advances 9 (2023): eadc9465.

[114] M. Holthaus, X. Xiong, K. Eghbalzadeh, et al., “Loss of Peptidylarginine Deiminase 4 Mitigates Maladaptive Cardiac Remodeling After Myocardial Infarction Through Inhibition of Inflammatory and Profibrotic Pathways,” Translational Research 280 (2025): 1–16.

[115] K. Martinod, T. Witsch, L. Erpenbeck, et al., “Peptidylarginine Deiminase 4 Promotes Age-related Organ Fibrosis,” Journal of Experimental Medicine 214 (2017): 439–458.

[116] K. Cai, F. Wang, J. Q. Lu, et al., “Nicotinamide Mononucleotide Alleviates Cardiomyopathy Phenotypes Caused by Short-Chain Enoyl-Coa Hydratase 1 Deficiency,” JACC: Basic to Translational Science 7 (2022): 348–362.

[117] A. W. Khan, F. Paneni, and K. A. M. Jandeleit-Dahm, “Cell-specific Epigenetic Changes in Atherosclerosis,” Clinical Science (London, England: 1979) 135 (2021): 1165–1187.

[118] L. P. Kajuluri, Y. Y. Guo, S. Lee, M. Christof, and R. Malhotra, “Epigenetic Regulation of Human Vascular Calcification,” Genes (Basel) 16 (2025): 506.

[119] Z. Chen, Y. Sun, P. Zhu, L. Zhang, J. Yang, and J. Zhang, “Role of Vascular Smooth Muscle Phenotypic Transformation Induced by Histone Modifications in the Development of Abdominal Aortic Aneurysms,” Clinical Epigenetics 17 (2025): 178.

[120] R. Chakraborty, A. C. Ostriker, Y. Xie, et al., “Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity,” Circulation 145 (2022): 1720–1737.

[121] A. Misra, Z. Feng, R. R. Chandran, et al., “Integrin beta3 Regulates Clonality and Fate of Smooth Muscle-derived Atherosclerotic Plaque Cells,” Nature Communications 9 (2018): 2073.

[122] R. C. Wirka, D. Wagh, D. T. Paik, et al., “Atheroprotective Roles of Smooth Muscle Cell Phenotypic Modulation and the TCF21 Disease Gene as Revealed by Single-cell Analysis,” Nature Medicine 25 (2019): 1280–1289.

[123] M. Liu, C. Espinosa-Diez, S. Mahan, et al., “H3K4 di-methylation Governs Smooth Muscle Lineage Identity and Promotes Vascular Homeostasis by Restraining Plasticity,” Developmental Cell 56 (2021): 2765–2782 e10.

[124] T. Yoshida, Q. Gan, and G. K. Owens, “Kruppel-Like Factor 4, Elk-1, and Histone Deacetylases Cooperatively Suppress Smooth Muscle Cell Differentiation Markers in Response to Oxidized Phospholipids,” American Journal of Physiology. Cell Physiology 295 (2008): C1175–C1182.

[125] M. Salmon, D. Gomez, E. Greene, L. Shankman, and G. K. Owens, “Cooperative Binding of KLF4, pELK-1, and HDAC2 to a G/C Repressor Element in the SM22α Promoter Mediates Transcriptional Silencing During SMC Phenotypic Switching in Vivo,” Circulation Research 111 (2012): 685–696.

[126] P. Chatterjee, R. Chakraborty, A. J. Sizer, et al., “SUV39H1 Regulates KLF4 and Chromatin Remodeling in Smooth Muscle Cell Phenotypic Plasticity,” Arteriosclerosis, Thrombosis, and Vascular Biology 45 (2025): 2015–2033.

[127] K. S. Heo, L. P. Phan, N. T. T. Le, and Y. Jin, “Mechanistic Insights and Emerging Therapeutic Strategies Targeting Endothelial Dysfunction in Cardiovascular Diseases,” Archives of Pharmacal Research 48 (2025): 305–332.

[128] J. C. Kovacic, S. Dimmeler, R. P. Harvey, et al., “Endothelial to Mesenchymal Transition in Cardiovascular Disease: JACC State-of-the-Art Review,” Journal of the American College of Cardiology 73 (2019): 190–209.

[129] L. Lecce, Y. Xu, B. V'Gangula, et al., “Histone Deacetylase 9 Promotes Endothelial-mesenchymal Transition and an Unfavorable Atherosclerotic Plaque Phenotype,” Journal of Clinical Investigation 131 (2021): e131178.

[130] C. L. Karthika, S. Ahalya, N. Radhakrishnan, C. C. Kartha, and S. Sumi, “Hemodynamics Mediated Epigenetic Regulators in the Pathogenesis of Vascular Diseases,” Molecular and Cellular Biochemistry 476 (2021): 125–143.

[131] M. S. Hulshoff, X. Xu, G. Krenning, and E. M. Zeisberg, “Epigenetic Regulation of Endothelial-to-Mesenchymal Transition in Chronic Heart Disease,” Arteriosclerosis, Thrombosis, and Vascular Biology 38 (2018): 1986–1996.

[132] M. Maleszewska, R. A. Gjaltema, G. Krenning, and M. C. Harmsen, “Enhancer of Zeste Homolog-2 (EZH2) Methyltransferase Regulates Transgelin/Smooth Muscle-22α Expression in Endothelial Cells in Response to Interleukin-1β and Transforming Growth Factor-β2,” Cell Signalling 27 (2015): 1589–1596.

[133] H. Dreger, A. Ludwig, A. Weller, et al., “Epigenetic Regulation of Cell Adhesion and Communication by Enhancer of Zeste Homolog 2 in human Endothelial Cells,” Hypertension 60 (2012): 1176–1183.

[134] S. F. Glaser, A. W. Heumüller, L. Tombor, et al., “The Histone Demethylase JMJD2B Regulates Endothelial-to-mesenchymal Transition,” Proceedings of the National Academy of Sciences of the United States of America 117 (2020): 4180–4187.

[135] B. Vanchin, M. Sol, R. A. F. Gjaltema, et al., “Reciprocal Regulation of Endothelial-mesenchymal Transition by MAPK7 and EZH2 in Intimal Hyperplasia and Coronary Artery Disease,” Scientific Reports 11 (2021): 17764.

[136] S. Costantino, F. Paneni, A. Virdis, et al., “Interplay Among H3K9-editing Enzymes SUV39H1, JMJD2C and SRC-1 Drives p66Shc Transcription and Vascular Oxidative Stress in Obesity,” European Heart Journal 40 (2019): 383–391.

[137] A. El-Osta, D. Brasacchio, D. Yao, et al., “Transient High Glucose Causes Persistent Epigenetic Changes and Altered Gene Expression During Subsequent Normoglycemia,” Journal of Experimental Medicine 205 (2008): 2409–2417.

[138] F. Paneni, S. Costantino, R. Battista, et al., “Adverse Epigenetic Signatures by Histone Methyltransferase Set7 Contribute to Vascular Dysfunction in Patients With Type 2 Diabetes Mellitus,” Circulation: Cardiovascular Genetics 8 (2015): 150–158.

[139] S. Masi, S. Ambrosini, S. A. Mohammed, et al., “Epigenetic Remodeling in Obesity-Related Vascular Disease,” Antioxidants & Redox Signaling 34 (2021): 1165–1199.

[140] M. Dong, Y. Zhang, M. Chen, et al., “ASF1A-dependent P300-mediated Histone H3 Lysine 18 Lactylation Promotes Atherosclerosis by Regulating EndMT,” Acta Pharmaceutica Sinica B 14 (2024): 3027–3048.

[141] J. E. Meegan, X. Yang, R. S. Beard, et al., “Citrullinated Histone 3 Causes Endothelial Barrier Dysfunction,” Biochemical and Biophysical Research Communications 503 (2018): 1498–1502.

[142] R. Osca-Verdegal, J. Beltrán-García, A. B. Paes, et al., “Histone Citrullination Mediates a Protective Role in Endothelium and Modulates Inflammation,” Cells 11 (2022): 4070.

[143] Y. J. Jin, G. Liang, R. Li, et al., “Phosphorylation of Endothelial Histone H3.3 Serine 31 by PKN1 Links Flow-induced Signaling to Proatherogenic Gene Expression,” Nature Cardiovascular Research 4 (2025): 180–196.

[144] J. Qin, N. Guo, J. Tong, and Z. Wang, “Function of Histone Methylation and Acetylation Modifiers in Cardiac Hypertrophy,” Journal of Molecular and Cellular Cardiology 159 (2021): 120–129.

[145] H. Ling, T. Zhang, L. Pereira, et al., “Requirement for Ca2+/Calmodulin-dependent Kinase II in the Transition From Pressure Overload-induced Cardiac Hypertrophy to Heart Failure in Mice,” Journal of Clinical Investigation 119 (2009): 1230–1240.

[146] J. C. K. Man, K. van Duijvenboden, P. H. L. Krijger, et al., “Genetic Dissection of a Super Enhancer Controlling the Nppa-Nppb Cluster in the Heart,” Circulation Research 128 (2021): 115–129.

[147] Z. Huang, S. Song, X. Zhang, L. Zeng, A. Sun, and J. Ge, “Metabolic Substrates, Histone Modifications, and Heart Failure,” Biochimica et Biophysica Acta Gene Regulatory Mechanisms 1866 (2023): 194898.

[148] B. E. Sansbury, A. M. DeMartino, Z. Xie, et al., “Metabolomic Analysis of Pressure-overloaded and Infarcted Mouse Hearts,” Circulation: Heart Failure 7 (2014): 634–642.

[149] J. Liu, Y. Jin, S. Zuo, et al., “Dot1L Promotes Stress-Induced Cardiac Hypertrophy in Mice via Tbx6,” Circulation Research 137 (2025): 496–512.

[150] R. J. Gusterson, E. Jazrawi, I. M. Adcock, and D. S. Latchman, “The Transcriptional co-activators CREB-binding Protein (CBP) and p300 Play a Critical Role in Cardiac Hypertrophy That Is Dependent on Their Histone Acetyltransferase Activity,” Journal of Biological Chemistry 278 (2003): 6838–6847.

[151] S. Miyamoto, T. Kawamura, T. Morimoto, et al., “Histone Acetyltransferase Activity of p300 Is Required for the Promotion of Left Ventricular Remodeling After Myocardial Infarction in Adult Mice in Vivo,” Circulation 113 (2006): 679–690.

[152] C. L. Zhang, T. A. McKinsey, S. Chang, C. L. Antos, J. A. Hill, and E. N. Olson, “Class II Histone Deacetylases Act as Signal-responsive Repressors of Cardiac Hypertrophy,” Cell 110 (2002): 479–488.

[153] Y. Katanasaka, Y. Sunagawa, R. Sakurai, et al., “Cardiac-specific Overexpression of PRMT5 Exacerbates Pressure Overload-induced Hypertrophy and Heart Failure,” Journal of Biomedical Science 32 (2025): 61.

[154] S. Awad, K. M. Al-Haffar, Q. Marashly, et al., “Control of Histone H3 Phosphorylation by CaMKIIδ in Response to Haemodynamic Cardiac Stress,” Journal of Pathology 235 (2015): 606–618.

[155] I. Y. Chen, J. Lypowy, J. Pain, et al., “Histone H2A.Z Is Essential for Cardiac Myocyte Hypertrophy but Opposed by Silent Information Regulator 2alpha,” Journal of Biological Chemistry 281 (2006): 19369–19377.

[156] M. A. Lorenzana-Carrillo, S. Tejay, J. Nanoa, et al., “TRIM35 Monoubiquitinates H2B in Cardiac Cells, Implications for Heart Failure,” Circulation Research 135 (2024): 301–313.

[157] Y. Q. Liu, Q. Yang, and G. W. He, “Post-translational Acylation of Proteins in Cardiac Hypertrophy,” Nature Reviews Cardiology 22 (2025): 944–960.

[158] M. Chen, Z. Wang, J. Li, et al., “Histone Lactylation Promotes Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure by Regulating TGFB2 Expression,” Circulation Research 138 (2026): e326185.

[159] X. Tang, X. F. Chen, X. Sun, et al., “Short-Chain Enoyl-CoA Hydratase Mediates Histone Crotonylation and Contributes to Cardiac Homeostasis,” Circulation 143 (2021): 1066–1069.

[160] Z. Ge, C. Yin, Y. Li, et al., “Long Noncoding RNA NEAT1 Promotes Cardiac Fibrosis in Heart Failure Through Increased Recruitment of EZH2 to the Smad7 Promoter Region,” Journal of Translational Medicine 20 (2022): 7.

[161] Q. R. Xu, J. L. Liu, R. R. Zhu, et al., “NSD2 promotes Pressure Overload-induced Cardiac Hypertrophy via Activating circCmiss1/TfR1/Ferroptosis Signaling,” Life Sciences 328 (2023): 121873.

[162] B. Thienpont, J. M. Aronsen, E. L. Robinson, et al., “The H3K9 Dimethyltransferases EHMT1/2 Protect Against Pathological Cardiac Hypertrophy,” Journal of Clinical Investigation 127 (2017): 335–348.

[163] L. Qi, X. Chi, X. Zhang, et al., “Kindlin-2 Suppresses Transcription Factor GATA4 Through Interaction With SUV39H1 to Attenuate Hypertrophy,” Cell Death & Disease 10 (2019): 890.

[164] D. Li, C. Zhang, J. Li, et al., “Long Non-coding RNA MALAT1 Promotes Cardiac Remodeling in Hypertensive Rats by Inhibiting the Transcription of MyoD,” Aging (Albany NY) 11 (2019): 8792–8809.

[165] R. Pane, L. Laib, K. Formoso, et al., “Macromolecular Complex Including MLL3, Carabin and Calcineurin Regulates Cardiac Remodeling,” Circulation Research 134 (2024): 100–113.

[166] S. Costantino, S. A. Mohammed, S. Ambrosini, et al., “Chromatin Rewiring by SETD2 Drives Lipotoxic Injury in Cardiometabolic HFpEF,” Circulation Research 136 (2025): 1079–1095.

[167] H. B. Su, J. H. Wang, Y. Y. Zhang, et al., “Inhibition of Setd7 Protects Against Cardiomyocyte Hypertrophy via Inhibiting Lipid Oxidation,” Acta Pharmacologica Sinica 47 (2026): 344–356.

[168] J. L. Huo, L. Jiao, Q. An, et al., “Myofibroblast Deficiency of LSD1 Alleviates TAC-Induced Heart Failure,” Circulation Research 129 (2021): 400–413.

[169] Q. J. Zhang, H. Z. Chen, L. Wang, D. P. Liu, J. A. Hill, and Z. P. Liu, “The Histone Trimethyllysine Demethylase JMJD2A Promotes Cardiac Hypertrophy in Response to Hypertrophic Stimuli in Mice,” Journal of Clinical Investigation 121 (2011): 2447–2456.

[170] M. Deogharia, L. Venegas-Zamora, A. Agrawal, et al., “Histone Demethylase KDM5 Regulates Cardiomyocyte Maturation by Promoting Fatty Acid Oxidation, Oxidative Phosphorylation, and Myofibrillar Organization,” Cardiovascular Research 120 (2024): 630–643.

[171] C. R. Morales, D. L. Li, Z. Pedrozo, et al., “Inhibition of Class I Histone Deacetylases Blunts Cardiac Hypertrophy Through TSC2-dependent mTOR Repression,” Science Signaling 9 (2016): ra34.

[172] V. Kesherwani, S. S. Nandi, S. K. Sharawat, H. R. Shahshahan, and P. K. Mishra, “Hydrogen Sulfide Mitigates Homocysteine-mediated Pathological Remodeling by Inducing miR-133a in Cardiomyocytes,” Molecular and Cellular Biochemistry 404 (2015): 241–250.

[173] C. M. Trivedi, Y. Luo, Z. Yin, et al., “Hdac2 regulates the Cardiac Hypertrophic Response by Modulating Gsk3 Beta Activity,” Nature Medicine 13 (2007): 324–331.

[174] H. Chen, Q. Lin, Y. Zeng, et al., “Xinyin Tablets Affect Mitophagy and Cardiomyocyte Apoptosis to Alleviate Chronic Heart Failure by Regulating Histone Deacetylase 3(HDAC3)-mediated PTEN Induced Putative Kinase 1(PINK1)/Parkin Signaling Pathway,” Journal of Ethnopharmacology 346 (2025): 119666.

[175] H. Zhou, H. J. Kee, L. Wan, et al., “YAK577 Attenuates Cardiac Remodeling and Fibrosis in Isoproterenol-Infused Heart Failure Mice by Downregulating MMP12,” Korean Circulation Journal 55 (2025): 231–247.

[176] T. Zhao, H. J. Kee, L. Bai, M. K. Kim, S. J. Kee, and M. H. Jeong, “Selective HDAC8 Inhibition Attenuates Isoproterenol-Induced Cardiac Hypertrophy and Fibrosis via p38 MAPK Pathway,” Frontiers in Pharmacology 12 (2021): 677757.

[177] X. Palomer, M. S. Román-Azcona, J. Pizarro-Delgado, et al., “SIRT3-mediated Inhibition of FOS Through Histone H3 Deacetylation Prevents Cardiac Fibrosis and Inflammation,” Signal Transduction and Targeted Therapy 5 (2020): 14.

[178] S. S. Yu, Y. Cai, J. T. Ye, et al., “Sirtuin 6 Protects Cardiomyocytes From Hypertrophy in Vitro via Inhibition of NF-κB-dependent Transcriptional Activity,” British Journal of Pharmacology 168 (2013): 117–128.

[179] R. Rai, S. K. Verma, D. Kim, et al., “A Novel Acetyltransferase p300 Inhibitor Ameliorates Hypertension-associated Cardio-renal Fibrosis,” Epigenetics 12 (2017): 1004–1013.

[180] E. L. Robinson, F. M. Drawnel, S. Mehdi, et al., “MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling With Early Gene Induction and Cardiac Hypertrophy,” Cells 11 (2022): 604.

[181] A. Kuno, R. Hosoda, M. Tsukamoto, et al., “SIRT1 in the Cardiomyocyte Counteracts Doxorubicin-induced Cardiotoxicity via Regulating Histone H2AX,” Cardiovascular Research 118 (2023): 3360–3373.

[182] X. Zhang, Y. Wang, J. Yuan, et al., “Macrophage/Microglial Ezh2 Facilitates Autoimmune Inflammation Through Inhibition of Socs3,” Journal of Experimental Medicine 215 (2018): 1365–1382.

[183] X. D. Meng, H. H. Yao, L. M. Wang, et al., “Knockdown of GAS5 Inhibits Atherosclerosis Progression via Reducing EZH2-Mediated ABCA1 Transcription in ApoE(-/-) Mice,” Molecular Therapy Nucleic Acids 19 (2020): 84–96.

[184] S. Xu, Y. Xu, M. Yin, et al., “Flow-dependent Epigenetic Regulation of IGFBP5 Expression by H3K27me3 Contributes to Endothelial Anti-inflammatory Effects,” Theranostics 8 (2018): 3007–3021.

[185] C. A. Bonfiglio, M. Lacy, V. Triantafyllidou, et al., “Ezh2 Shapes T Cell Plasticity to Drive Atherosclerosis,” Circulation 151 (2025): 1391–1408.

[186] A. E. Neele, K. H. Prange, M. A. Hoeksema, et al., “Macrophage Kdm6b Controls the Pro-fibrotic Transcriptome Signature of Foam Cells,” Epigenomics 9 (2017): 383–391.

[187] N. Zhu, Z. F. Guo, K. Kazama, et al., “Epigenetic Regulation of Vascular Smooth Muscle Cell Phenotypic Switch and Neointimal Formation by PRMT5,” Cardiovascular Research 119 (2023): 2244–2255.

[188] S. Zhang, Y. Sun, Q. Xiao, M. Niu, X. Pan, and X. Zhu, “Lnc_000048 Promotes Histone H3K4 Methylation of MAP2K2 to Reduce Plaque Stability by Recruiting KDM1A in Carotid Atherosclerosis,” Molecular Neurobiology 60 (2023): 2572–2586.

[189] J. Wang, X. Xu, P. Li, B. Zhang, and J. Zhang, “HDAC3 protects Against Atherosclerosis Through Inhibition of Inflammation via the microRNA-19b/PPARγ/NF-κB Axis,” Atherosclerosis 323 (2021): 1–12.

[190] Y. Zhang, H. Jiang, M. Dong, et al., “Macrophage MCT4 Inhibition Activates Reparative Genes and Protects From Atherosclerosis by Histone H3 Lysine 18 Lactylation,” Cell Reports 43 (2024): 114180.

[191] X. Li, M. Chen, X. Chen, et al., “TRAP1 drives Smooth Muscle Cell Senescence and Promotes Atherosclerosis via HDAC3-primed Histone H4 Lysine 12 Lactylation,” European Heart Journal 45 (2024): 4219–4235.

[192] Y. Liu, C. Carmona-Rivera, E. Moore, et al., “Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis,” Frontiers in Immunology 9 (2018): 1680.

[193] F. Chang, C. Wang, P. Zheng, et al., “Malat1 promotes Macrophage-associated Inflammation by Increasing PPAR-γ Methylation Through Binding to EZH2 in Acute Myocardial Infarction,” International Immunopharmacology 123 (2023): 110695.

[194] J. Rondeaux, D. Groussard, S. Renet, et al., “Ezh2 emerges as an Epigenetic Checkpoint Regulator During Monocyte Differentiation Limiting Cardiac Dysfunction Post-MI,” Nature Communications 14 (2023): 4461.

[195] G. Yang, X. Weng, Y. Zhao, et al., “The Histone H3K9 Methyltransferase SUV39H Links SIRT1 Repression to Myocardial Infarction,” Nature Communications 8 (2017): 14941.

[196] S. Xing, J. Z. Tian, S. H. Yang, et al., “Setd4 controlled Quiescent c-Kit(+) Cells Contribute to Cardiac Neovascularization of Capillaries Beyond Activation,” Scientific Reports 11 (2021): 11603.

[197] J. Xu, J. Wang, F. Long, et al., “Inhibition of the Cardiac Fibroblast-enriched Histone Methyltransferase Dot1L Prevents Cardiac Fibrosis and Cardiac Dysfunction,” Cell BioSciences 12 (2022): 134.

[198] F. Li, L. Li, J. Zhang, X. Yang, and Y. Liu, “Histone Methyltransferase DOT1L Mediates the TGF-β1/Smad3 Signaling Pathway Through Epigenetic Modification of SYK in Myocardial Infarction,” Human Cell 35 (2022): 98–110.

[199] B. Wang, Y. Tan, Y. Zhang, et al., “Loss of KDM5B Ameliorates Pathological Cardiac Fibrosis and Dysfunction by Epigenetically Enhancing ATF3 Expression,” Experimental & Molecular Medicine 54 (2022): 2175–2187.

[200] P. R. Nagareddy, G. Sreejit, M. Abo-Aly, et al., “NETosis Is Required for S100A8/A9-Induced Granulopoiesis after Myocardial Infarction,” Arteriosclerosis, Thrombosis, and Vascular Biology 40 (2020): 2805–2807.

[201] O. Gidlöf, A. L. Johnstone, K. Bader, et al., “Ischemic Preconditioning Confers Epigenetic Repression of Mtor and Induction of Autophagy through G9a-Dependent H3K9 Dimethylation,” Journal of the American Heart Association 5 (2016): e004076.

[202] G. Yang, X. Zhang, X. Weng, et al., “SUV39H1 mediated SIRT1 Trans-repression Contributes to Cardiac Ischemia-reperfusion Injury,” Basic Research in Cardiology 112 (2017): 22.

[203] Y. Dang, X. Ma, Y. Li, et al., “Inhibition of SETD7 Protects Cardiomyocytes Against Hypoxia/Reoxygenation-induced Injury Through Regulating Keap1/Nrf2 Signaling,” Biomedicine & Pharmacotherapy 106 (2018): 842–849.

[204] Y. Cao, F. Luo, J. Peng, Z. Fang, Q. Liu, and S. Zhou, “KMT2B-dependent RFK Transcription Activates the TNF-α/NOX2 Pathway and Enhances Ferroptosis Caused by Myocardial Ischemia-reperfusion,” Journal of Molecular and Cellular Cardiology 173 (2022): 75–91.

[205] F. Liu, Y. Di, W. Ma, X. Kang, X. Li, and Z. Ji, “HDAC9 exacerbates Myocardial Infarction via Inactivating Nrf2 Pathways,” Journal of Pharmacy and Pharmacology 74 (2022): 565–572.

[206] Z. Li, X. Zhang, S. Liu, et al., “BRG1 regulates NOX Gene Transcription in Endothelial Cells and Contributes to Cardiac Ischemia-reperfusion Injury,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1864 (2018): 3477–3486.

[207] P. Shi, J. Wu, M. Li, et al., “Upregulation of Hsp27 via Further Inhibition of Histone H2A Ubiquitination Confers Protection Against Myocardial Ischemia/Reperfusion Injury by Promoting Glycolysis and Enhancing Mitochondrial Function,” Cell Death Discovery 9 (2023): 466.

[208] W. Zhang, Q. Wang, X. Xing, et al., “The Antagonistic Effects and Mechanisms of microRNA-26a Action in Hypertensive Vascular Remodelling,” British Journal of Pharmacology 178 (2021): 1037–1054.

[209] K. D. Mangum, Q. Li, K. Hartmann, et al., “Epigenetic Alteration of Smooth Muscle Cells Regulates Endothelin-dependent Blood Pressure and Hypertensive Arterial Remodeling,” Journal of Clinical Investigation 135 (2025): e186146.

[210] T. Treesaranuwattana, K. Y. H. Wong, D. L. Brooks, et al., “Lysine-Specific Demethylase-1 Deficiency Increases Agonist Signaling via the Mineralocorticoid Receptor,” Hypertension 75 (2020): 1045–1053.

[211] W. Zhang, X. Xia, M. R. Reisenauer, et al., “Aldosterone-induced Sgk1 Relieves Dot1a-Af9-mediated Transcriptional Repression of Epithelial Na+ Channel Alpha,” Journal of Clinical Investigation 117 (2007): 773–783.

[212] C. W. Yancy, M. Jessup, B. Bozkurt, et al., “2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” Journal of the American College of Cardiology 62 (2013): e147–e239.

[213] M. Nakamura and J. Sadoshima, “Mechanisms of Physiological and Pathological Cardiac Hypertrophy,” Nature Reviews Cardiology 15 (2018): 387–407.

[214] J. G. Travers, F. A. Kamal, J. Robbins, K. E. Yutzey, and B. C. Blaxall, “Cardiac Fibrosis: The Fibroblast Awakens,” Circulation Research 118 (2016): 1021–1040.

[215] F. Long, Q. Wang, D. Yang, et al., “Targeting JMJD3 Histone Demethylase Mediates Cardiac Fibrosis and Cardiac Function Following Myocardial Infarction,” Biochemical and Biophysical Research Communications 528 (2020): 671–677.

[216] C. F. Liu, A. Abnousi, P. Bazeley, et al., “Global Analysis of Histone Modifications and Long-range Chromatin Interactions Revealed the Differential Cistrome Changes and Novel Transcriptional Players in human Dilated Cardiomyopathy,” Journal of Molecular and Cellular Cardiology 145 (2020): 30–42.

[217] P. Syren, A. K. Rahm, P. A. Schweizer, et al., “Histone Deacetylase 2-dependent Ventricular Electrical Remodeling in a Porcine Model of Early Heart Failure,” Life Sciences 281 (2021): 119769.

[218] M. Hohl, M. Wagner, J. C. Reil, et al., “HDAC4 controls Histone Methylation in Response to Elevated Cardiac Load,” Journal of Clinical Investigation 123 (2013): 1359–1370.

[219] K. Tian, Z. Liu, J. Wang, S. Xu, T. You, and P. Liu, “Sirtuin-6 Inhibits Cardiac Fibroblasts Differentiation Into Myofibroblasts via Inactivation of Nuclear Factor κB Signaling,” Translational Research 165 (2015): 374–386.

[220] A. R. Saadatmand, V. Sramek, S. Weber, et al., “CaM Kinase II Regulates Cardiac Hemoglobin Expression Through Histone Phosphorylation Upon Sympathetic Activation,” Proceedings of the National Academy of Sciences of the United States of America 116 (2019): 22282–22287.

[221] P. Libby, P. M. Ridker, and A. Maseri, “Inflammation and Atherosclerosis,” Circulation 105 (2002): 1135–1143.

[222] I. Tabas, G. García-Cardeña, and G. K. Owens, “Recent Insights Into the Cellular Biology of Atherosclerosis,” Journal of Cell Biology 209 (2015): 13–22.

[223] A. E. Neele, H. J. Chen, M. J. J. Gijbels, et al., “Myeloid Ezh2 Deficiency Limits Atherosclerosis Development,” Frontiers in Immunology 11 (2020): 594603.

[224] S. Fadaei, F. Zarepour, M. Parvaresh, et al., “Epigenetic Regulation in Myocardial Infarction: Non-coding RNAs and Exosomal Non-coding RNAs,” Frontiers in Cardiovascular Medicine 9 (2022): 1014961.

[225] L. Yao, F. He, Q. Zhao, et al., “Spatial Multiplexed Protein Profiling of Cardiac Ischemia-Reperfusion Injury,” Circulation Research 133 (2023): 86–103.

[226] J. Li, X. Chen, R. McClusky, et al., “The Number of X Chromosomes Influences Protection From Cardiac Ischaemia/Reperfusion Injury in Mice: One X Is Better Than Two,” Cardiovascular Research 102 (2014): 375–384.

[227] I. A. M. Brown, L. Diederich, M. E. Good, et al., “Vascular Smooth Muscle Remodeling in Conductive and Resistance Arteries in Hypertension,” Arteriosclerosis, Thrombosis, and Vascular Biology 38 (2018): 1969–1985.

[228] J. P. Cardinale, S. Sriramula, R. Pariaut, et al., “HDAC Inhibition Attenuates Inflammatory, Hypertrophic, and Hypertensive Responses in Spontaneously Hypertensive Rats,” Hypertension 56 (2010): 437–444.

[229] H. J. Kee, G. R. Kim, M. Q. Lin, et al., “Expression of Class I and Class II a/b Histone Deacetylase Is Dysregulated in Hypertensive Animal Models,” Korean Circulation Journal 47 (2017): 392–400.

[230] T. M. Lee, M. S. Lin, and N. C. Chang, “Inhibition of Histone Deacetylase on Ventricular Remodeling in Infarcted Rats,” American Journal of Physiology. Heart and Circulatory Physiology 293 (2007): H968–H977.

[231] S. Ranjbarvaziri, A. Zeng, I. Wu, et al., “Targeting HDAC6 to Treat Heart Failure With Preserved Ejection Fraction in Mice,” Nature Communications 15 (2024): 1352.

[232] L. Zhao, C. N. Chen, N. Hajji, et al., “Histone Deacetylation Inhibition in Pulmonary Hypertension: Therapeutic Potential of Valproic Acid and Suberoylanilide Hydroxamic Acid,” Circulation 126 (2012): 455–467.

[233] R. L. Benza, P. B. Adamson, D. L. Bhatt, et al., “CS1, a Controlled-release Formulation of Valproic Acid, for the Treatment of Patients With Pulmonary Arterial Hypertension: Rationale and Design of a Phase 2 Clinical Trial,” Pulmonary Circulation 14 (2024): e12323.

[234] J. F. San-Miguel, V. T. Hungria, S. S. Yoon, et al., “Panobinostat plus bortezomib and Dexamethasone versus Placebo plus Bortezomib and Dexamethasone in Patients With Relapsed or Relapsed and Refractory Multiple Myeloma: A Multicentre, Randomised, Double-blind Phase 3 Trial,” The Lancet Oncology 15 (2014): 1195–1206.

[235] L. M. Tsujikawa, L. Fu, S. Das, et al., “Apabetalone (RVX-208) Reduces Vascular Inflammation in Vitro and in CVD Patients by a BET-dependent Epigenetic Mechanism,” Clin Epigenetics 11 (2019): 102.

[236] S. J. Nicholls, R. Puri, K. Wolski, et al., “Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b, Randomized, Double-Blind, Multicenter, ASSURE Trial,” American Journal of Cardiovascular Drugs 16 (2016): 55–65.

[237] K. K. Ray, S. J. Nicholls, K. A. Buhr, et al., “Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients with Recent Acute Coronary Syndrome and Type 2 Diabetes: A Randomized Clinical Trial,” Jama 323 (2020): 1565–1573.

[238] S. Provencher, F. Potus, P. Blais-Lecours, et al., “BET Protein Inhibition for Pulmonary Arterial Hypertension: A Pilot Clinical Trial,” American Journal of Respiratory and Critical Care Medicine 205 (2022): 1357–1360.

[239] S. A. Piha-Paul, C. L. Hann, C. A. French, et al., “Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors,” JNCI Cancer Spectrum 4 (2020): pkz093.

[240] S. Aziz, L. Yalan, M. A. Raza, J. Lemin, H. M. B. Akram, and W. Zhao, “GSK126 an Inhibitor of Epigenetic Regulator EZH2 Suppresses Cardiac Fibrosis by Regulating the EZH2-PAX6-CXCL10 Pathway,” Biochemistry and Cell Biology 101 (2023): 87–100.

[241] Z. Guo, J. Lu, J. Li, et al., “JMJD3 inhibition Protects Against Isoproterenol-induced Cardiac Hypertrophy by Suppressing β-MHC Expression,” Molecular and Cellular Endocrinology 477 (2018): 1–14.

[242] A. Italiano, J. C. Soria, M. Toulmonde, et al., “Tazemetostat, an EZH2 Inhibitor, in Relapsed or Refractory B-cell Non-Hodgkin Lymphoma and Advanced Solid Tumours: A First-in-human, Open-label, Phase 1 Study,” The Lancet Oncology 19 (2018): 649–659.

[243] M. Gounder, P. Schöffski, R. L. Jones, et al., “Tazemetostat in Advanced Epithelioid Sarcoma With Loss of INI1/SMARCB1: An International, Open-label, Phase 2 Basket Study,” The Lancet Oncology 21 (2020): 1423–1432.

[244] E. M. Stein, G. Garcia-Manero, D. A. Rizzieri, et al., “The DOT1L Inhibitor Pinometostat Reduces H3K79 Methylation and Has Modest Clinical Activity in Adult Acute Leukemia,” Blood 131 (2018): 2661–2669.

[245] H. Su, H. Zeng, X. He, S. H. Zhu, and J. X. Chen, “Histone Acetyltransferase p300 Inhibitor Improves Coronary Flow Reserve in SIRT3 (Sirtuin 3) Knockout Mice,” Journal of the American Heart Association 9 (2020): e017176.

[246] P. Chun, “Therapeutic Effects of Histone Deacetylase Inhibitors on Heart Disease,” Archives of Pharmacal Research 43 (2020): 1276–1296.

[247] J. Lu, S. Qian, and Z. Sun, “Targeting Histone Deacetylase in Cardiac Diseases,” Frontiers in Physiology 15 (2024): 1405569.

[248] H. J. Kee, I. S. Sohn, K. I. Nam, et al., “Inhibition of Histone Deacetylation Blocks Cardiac Hypertrophy Induced by angiotensin II Infusion and Aortic Banding,” Circulation 113 (2006): 51–59.

[249] T. A. McKinsey, “Targeting Inflammation in Heart Failure With Histone Deacetylase Inhibitors,” Molecular Medicine 17 (2011): 434–441.

[250] S. M. Williams, L. Golden-Mason, B. S. Ferguson, et al., “Class I HDACs Regulate Angiotensin II-dependent Cardiac Fibrosis via Fibroblasts and Circulating Fibrocytes,” Journal of Molecular and Cellular Cardiology 67 (2014): 112–125.

[251] J. Habibian and B. S. Ferguson, “The Crosstalk Between Acetylation and Phosphorylation: Emerging New Roles for HDAC Inhibitors in the Heart,” International Journal of Molecular Sciences 20 (2018): 102.

[252] A. Granger, I. Abdullah, F. Huebner, et al., “Histone Deacetylase Inhibition Reduces Myocardial Ischemia-reperfusion Injury in Mice,” Faseb Journal 22 (2008): 3549–3560.

[253] D. Kimbrough, S. H. Wang, L. H. Wright, et al., “HDAC Inhibition Helps Post-MI Healing by Modulating Macrophage Polarization,” Journal of Molecular and Cellular Cardiology 119 (2018): 51–63.

[254] L. Zhang, B. Chen, Y. Zhao, et al., “Inhibition of Histone Deacetylase-induced Myocardial Repair Is Mediated by c-kit in Infarcted Hearts,” Journal of Biological Chemistry 287 (2012): 39338–39348.

[255] K. K. W. To, S. S. Tolu, L. Wang, H. Zhang, W. C. Cho, and S. E. Bates, “HDAC Inhibitors: Cardiotoxicity and Paradoxical Cardioprotective Effect in Ischemia-reperfusion Myocardiocyte Injury,” Seminars in Cancer Biology 113 (2025): 25–38.

[256] O. A. O'Connor, S. Horwitz, T. Masszi, et al., “Belinostat in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study,” Journal of Clinical Oncology 33 (2015): 2492–2499.

[257] S. Rai, W. S. Kim, K. Ando, et al., “Oral HDAC Inhibitor Tucidinostat in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma: Phase IIb Results,” Haematologica 108 (2023): 811–821.

[258] S. Spence, M. Deurinck, H. Ju, et al., “Histone Deacetylase Inhibitors Prolong Cardiac Repolarization Through Transcriptional Mechanisms,” Toxicological Sciences 153 (2016): 39–54.

[259] M. Wallner, D. M. Eaton, R. M. Berretta, et al., “HDAC Inhibition Improves Cardiopulmonary Function in a Feline Model of Diastolic Dysfunction,” Science Translational Medicine 12 (2020): eaay7205.

[260] J. G. Travers, S. A. Wennersten, B. Peña, et al., “HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling,” Circulation 143 (2021): 1874–1890.

[261] Q. Duan, S. McMahon, P. Anand, et al., “BET Bromodomain Inhibition Suppresses Innate Inflammatory and Profibrotic Transcriptional Networks in Heart Failure,” Science Translational Medicine 9 (2017): eaah5084.

[262] Y. Wu, M. Zhang, C. Xu, D. Chai, F. Peng, and J. Lin, “Anti-Diabetic Atherosclerosis by Inhibiting High Glucose-Induced Vascular Smooth Muscle Cell Proliferation via Pin1/BRD4 Pathway,” Oxidative Medicine and Cellular Longevity 2020 (2020): 4196482.

[263] S. Picaud, C. Wells, I. Felletar, et al., “RVX-208, an Inhibitor of BET Transcriptional Regulators With Selectivity for the Second Bromodomain,” Proceedings of the National Academy of Sciences of the United States of America 110 (2013): 19754–19759.

[264] K. G. McLure, E. M. Gesner, L. Tsujikawa, et al., “RVX-208, an Inducer of ApoA-I in Humans, Is a BET Bromodomain Antagonist,” PLoS ONE 8 (2013): e83190.

[265] J. Meloche, F. Potus, M. Vaillancourt, et al., “Bromodomain-Containing Protein 4: The Epigenetic Origin of Pulmonary Arterial Hypertension,” Circulation Research 117 (2015): 525–535.

[266] D. E. Van der Feen, K. Kurakula, E. Tremblay, et al., “Multicenter Preclinical Validation of BET Inhibition for the Treatment of Pulmonary Arterial Hypertension,” American Journal of Respiratory and Critical Care Medicine 200 (2019): 910–920.

[267] M. A. Dawson, G. Borthakur, B. J. P. Huntly, et al., “A Phase I/II Open-Label Study of Molibresib for the Treatment of Relapsed/Refractory Hematologic Malignancies,” Clinical Cancer Research 29 (2023): 711–722.

[268] J. Y. Zhu, J. van de Leemput, and Z. Han, “The Roles of Histone Lysine Methyltransferases in Heart Development and Disease,” Journal of Cardiovascular Development and Disease 10 (2023): 305.

[269] K. Davis, P. Azarcon, S. Hickenlooper, et al., “The Role of Demethylases in Cardiac Development and Disease,” Journal of Molecular and Cellular Cardiology 158 (2021): 89–100.

[270] C. Mascaró, A. Ortega, E. Carceller, et al., “Chemoprobe-based Assays of Histone Lysine Demethylase 1A Target Occupation Enable in Vivo Pharmacokinetics and Pharmacodynamics Studies of KDM1A Inhibitors,” Journal of Biological Chemistry 294 (2019): 8311–8322.

[271] K. Chen, D. Jian, L. Zhao, et al., “Protective Effect of Histone Methyltransferase NSD3 on ISO-induced Cardiac Hypertrophy,” Febs Letters 593 (2019): 2556–2565.

[272] X. M. Meng, Q. Y. Pang, Z. F. Zhou, et al., “Histone Methyltransferase MLL4 Protects Against Pressure Overload-induced Heart Failure via a THBS4-mediated Protection in ER Stress,” Pharmacological Research 205 (2024): 107263.

[273] F. Morschhauser, H. Tilly, A. Chaidos, et al., “Tazemetostat for Patients With Relapsed or Refractory Follicular Lymphoma: An Open-label, Single-arm, Multicentre, Phase 2 Trial,” The Lancet Oncology 21 (2020): 1433–1442.

[274] H. Zhang, J. Zhao, J. Yu, et al., “Lactate Metabolism and Lactylation in Cardiovascular Disease: Novel Mechanisms and Therapeutic Targets,” Frontiers in Cardiovascular Medicine 11 (2024): 1489438.

[275] S. S. Zhao, J. Liu, Q. C. Wu, and X. L. Zhou, “Lactate Regulates Pathological Cardiac Hypertrophy via Histone Lactylation Modification,” Journal of Cellular and Molecular Medicine 28 (2024): e70022.

[276] C. Moreno-Yruela, D. Zhang, W. Wei, et al., “Class I Histone Deacetylases (HDAC1-3) Are Histone Lysine Delactylases,” Science Advances 8 (2022): eabi6696.

[277] W. Wei, X. Liu, J. Chen, et al., “Class I Histone Deacetylases Are Major Histone Decrotonylases: Evidence for Critical and Broad Function of Histone Crotonylation in Transcription,” Cell Research 27 (2017): 898–915.

[278] X. Bao, Y. Wang, X. Li, et al., “Identification of ‘Erasers’ for Lysine Crotonylated Histone Marks Using a Chemical Proteomics Approach,” Elife 3 (2014): e02999.

[279] R. Zhu, X. Ye, X. Lu, et al., “ACSS2 acts as a Lactyl-CoA Synthetase and Couples KAT2A to Function as a Lactyltransferase for Histone Lactylation and Tumor Immune Evasion,” Cell Metabolism 37 (2025): 361-376 e7.

[280] Z. Niu, C. Chen, S. Wang, et al., “HBO1 catalyzes Lysine Lactylation and Mediates Histone H3K9la to Regulate Gene Transcription,” Nature Communications 15 (2024): 3561.

[281] Q. Zhang, L. Zeng, C. Zhao, Y. Ju, T. Konuma, and M. M. Zhou, “Structural Insights Into Histone Crotonyl-Lysine Recognition by the AF9 YEATS Domain,” Structure (London, England) 24 (2016): 1606–1612.

[282] T. Christott, J. Bennett, C. Coxon, et al., “Discovery of a Selective Inhibitor for the YEATS Domains of ENL/AF9,” SLAS Discovery 24 (2019): 133–141.

[283] L. A. Gilbert, M. H. Larson, L. Morsut, et al., “CRISPR-mediated Modular RNA-guided Regulation of Transcription in Eukaryotes,” Cell 154 (2013): 442–451.

[284] I. B. Hilton, A. M. D'Ippolito, C. M. Vockley, et al., “Epigenome Editing by a CRISPR-Cas9-based Acetyltransferase Activates Genes From Promoters and Enhancers,” Nature Biotechnology 33 (2015): 510–517.

[285] N. A. Kearns, H. Pham, B. Tabak, et al., “Functional Annotation of Native Enhancers With a Cas9-histone Demethylase Fusion,” Nature Methods 12 (2015): 401–403.

[286] L. S. Qi, M. H. Larson, L. A. Gilbert, et al., “Repurposing CRISPR as an RNA-guided Platform for Sequence-specific Control of Gene Expression,” Cell 152 (2013): 1173–1183.

[287] M. P. Gemberling, K. Siklenka, E. Rodriguez, et al., “Transgenic Mice for in Vivo Epigenome Editing With CRISPR-based Systems,” Nature Methods 18 (2021): 965–974.

[288] C. H. Lau and Y. Suh, “In Vivo Epigenome Editing and Transcriptional Modulation Using CRISPR Technology,” Transgenic Research 27 (2018): 489–509.

[289] J. K. Nuñez, J. Chen, G. C. Pommier, et al., “Genome-wide Programmable Transcriptional Memory by CRISPR-based Epigenome Editing,” Cell 184 (2021): 2503–2519 e17.

[290] Y. Zhou, L. Wang, H. R. Vaseghi, et al., “Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming,” Cell Stem Cell 18 (2016): 382–395.

[291] M. Ieda, J. D. Fu, P. Delgado-Olguin, et al., “Direct Reprogramming of Fibroblasts Into Functional Cardiomyocytes by Defined Factors,” Cell 142 (2010): 375–386.

[292] L. Qian, Y. Huang, C. I. Spencer, et al., “In Vivo Reprogramming of Murine Cardiac Fibroblasts Into Induced Cardiomyocytes,” Nature 485 (2012): 593–598.

[293] K. Song, Y. J. Nam, X. Luo, et al., “Heart Repair by Reprogramming Non-myocytes With Cardiac Transcription Factors,” Nature 485 (2012): 599–604.

[294] T. M. Jayawardena, B. Egemnazarov, E. A. Finch, et al., “MicroRNA-mediated in Vitro and in Vivo Direct Reprogramming of Cardiac Fibroblasts to Cardiomyocytes,” Circulation Research 110 (2012): 1465–1473.

[295] J. X. Chen, M. Krane, M. A. Deutsch, et al., “Inefficient Reprogramming of Fibroblasts Into Cardiomyocytes Using Gata4, Mef2c, and Tbx5,” Circulation Research 111 (2012): 50–55.

[296] L. Jiang, J. Liang, W. Huang, et al., “CRISPR Activation of Endogenous Genes Reprograms Fibroblasts Into Cardiovascular Progenitor Cells for Myocardial Infarction Therapy,” Molecular Therapy 30 (2022): 54–74.

[297] P. Huang, J. Xu, B. Keepers, et al., “Direct Cardiac Reprogramming via Combined CRISPRa-mediated Endogenous Gata4 Activation and Exogenous Mef2c and Tbx5 Expression,” Molecular Therapy Nucleic Acids 35 (2024): 102390.

[298] E. Karbassi, R. Padgett, A. Bertero, et al., “Targeted CRISPR Activation Is Functional in Engineered human Pluripotent Stem Cells but Undergoes Silencing After Differentiation Into Cardiomyocytes and Endothelium,” Cellular and Molecular Life Sciences 81 (2024): 95.

[299] J. D. Gillmore, E. Gane, J. Taubel, et al., “CRISPR-Cas9 in Vivo Gene Editing for Transthyretin Amyloidosis,” New England Journal of Medicine 385 (2021): 493–502.

[300] R. G. Lee, A. M. Mazzola, M. C. Braun, et al., “Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting PCSK9 in Nonhuman Primate and Mouse Models,” Circulation 147 (2023): 242–253.

[301] A. Blasco, A. Rosell, R. Castejón, et al., “Inflammatory and Neutrophil Extracellular Trap Markers to Predict Cardiac Events After ST-segment Elevation Myocardial Infarction,” PLoS ONE 20 (2025): e0319759.

[302] A. Mangold, S. Alias, T. Scherz, et al., “Coronary Neutrophil Extracellular Trap Burden and Deoxyribonuclease Activity in ST-elevation Acute Coronary Syndrome Are Predictors of ST-segment Resolution and Infarct Size,” Circulation Research 116 (2015): 1182–1192.

[303] A. Blasco, M. J. Coronado, P. Vela, et al., “Prognostic Implications of Neutrophil Extracellular Traps in Coronary Thrombi of Patients With ST-Elevation Myocardial Infarction,” Thrombosis and Haemostasis 122 (2022): 1415–1428.

[304] D. Shishikura, Y. Kataoka, S. Honda, et al., “The Effect of Bromodomain and Extra-Terminal Inhibitor Apabetalone on Attenuated Coronary Atherosclerotic Plaque: Insights From the ASSURE Trial,” American Journal of Cardiovascular Drugs 19 (2019): 49–57.

[305] S. J. Nicholls, K. K. Ray, J. O. Johansson, et al., “Selective BET Protein Inhibition With Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients With Coronary Artery Disease,” American Journal of Cardiovascular Drugs 18 (2018): 109–115.

[306] S. J. Nicholls, G. G. Schwartz, K. A. Buhr, et al., “Apabetalone and Hospitalization for Heart Failure in Patients Following an Acute Coronary Syndrome: A Prespecified Analysis of the BETonMACE Study,” Cardiovascular Diabetology 20 (2021): 13.

[307] O. Saluveer, P. Larsson, W. Ridderstråle, T. J. Hrafnkelsdóttir, S. Jern, and N. Bergh, “Profibrinolytic Effect of the Epigenetic Modifier Valproic Acid in Man,” PLoS ONE 9 (2014): e107582.

[308] K. Svennerholm, M. Haney, B. Biber, et al., “Histone Deacetylase Inhibition Enhances Tissue Plasminogen Activator Release Capacity in Atherosclerotic Man,” PLoS ONE 10 (2015): e0121196.

[309] J. Bai, P. Jiang, L. Ji, et al., “Histone Modifications of Circulating Nucleosomes Are Associated With Changes in Cell-free DNA Fragmentation Patterns,” Proceedings of the National Academy of Sciences of the United States of America 121 (2024): e2404058121.

[310] W. L. W. Tan, C. G. Anene-Nzelu, E. Wong, et al., “Epigenomes of Human Hearts Reveal New Genetic Variants Relevant for Cardiac Disease and Phenotype,” Circulation Research 127 (2020): 761–777.

[311] J. Pei, M. Harakalova, T. A. Treibel, et al., “H3K27ac acetylome Signatures Reveal the Epigenomic Reorganization in Remodeled Non-failing human Hearts,” Clinical Epigenetics 12 (2020): 106.

[312] J. E. Tisdale, M. K. Chung, K. B. Campbell, et al., “Drug-Induced Arrhythmias: A Scientific Statement from the American Heart Association,” Circulation 142 (2020): e214–e233.

[313] J. J. Maly, B. A. Christian, X. Zhu, et al., “A Phase I/II Trial of Panobinostat in Combination with Lenalidomide in Patients with Relapsed or Refractory Hodgkin Lymphoma,” Clinical Lymphoma, Myeloma & Leukemia 17 (2017): 347–353.

[314] S. B. Rothbart, B. M. Dickson, J. R. Raab, et al., “An Interactive Database for the Assessment of Histone Antibody Specificity,” Molecular Cell 59 (2015): 502–511.

[315] P. J. Skene and S. Henikoff, “An Efficient Targeted Nuclease Strategy for High-resolution Mapping of DNA Binding Sites,” Elife 6 (2017): e21856.

[316] S. Nishikori, T. Hattori, S. M. Fuchs, et al., “Broad Ranges of Affinity and Specificity of Anti-histone Antibodies Revealed by a Quantitative Peptide Immunoprecipitation Assay,” Journal of Molecular Biology 424 (2012): 391–399.

[317] I. Bock, A. Dhayalan, S. Kudithipudi, O. Brandt, P. Rathert, and A. Jeltsch, “Detailed Specificity Analysis of Antibodies Binding to Modified Histone Tails With Peptide Arrays,” Epigenetics 6 (2011): 256–263.

[318] S. M. Fuchs and B. D. Strahl, “Antibody Recognition of Histone Post-translational Modifications: Emerging Issues and Future Prospects,” Epigenomics 3 (2011): 247–249.

[319] S. M. Fuchs, K. Krajewski, R. W. Baker, V. L. Miller, and B. D. Strahl, “Influence of Combinatorial Histone Modifications on Antibody and Effector Protein Recognition,” Current Biology 21 (2011): 53–58.

[320] H. S. Kaya-Okur, S. J. Wu, C. A. Codomo, et al., “CUT&Tag for Efficient Epigenomic Profiling of Small Samples and Single Cells,” Nature Communications 10 (2019): 1930.

[321] L. M. Britton, M. Gonzales-Cope, B. M. Zee, and B. A. Garcia, “Breaking the Histone Code With Quantitative Mass Spectrometry,” Expert Review of Proteomics 8 (2011): 631–643.

[322] T. M. Maile, A. Izrael-Tomasevic, T. Cheung, et al., “Mass Spectrometric Quantification of Histone Post-translational Modifications by a Hybrid Chemical Labeling Method,” Molecular & Cellular Proteomics 14 (2015): 1148–1158.

[323] L. Kollenstart, S. C. van der Horst, K. Vreeken, et al., “Epigenetics Identifier Screens Reveal Regulators of Chromatin Acylation and Limited Specificity of Acylation Antibodies,” Scientific Reports 11 (2021): 12795.

[324] S. Nitsch, L. Zorro Shahidian, and R. Schneider, “Histone Acylations and Chromatin Dynamics: Concepts, Challenges, and Links to Metabolism,” Embo Reports 22 (2021): e52774.

[325] G. Goens, D. Rusu, L. Bultot, J. J. Goval, and J. Magdalena, “Characterization and Quality Control of Antibodies Used in ChIP Assays,” Methods in Molecular Biology 567 (2009): 27–43.

[326] J. D. Hocker, O. B. Poirion, F. Zhu, et al., “Cardiac Cell Type-specific Gene Regulatory Programs and Disease Risk Association,” Science Advances 7 (2021): eabf1444.

[327] A. W. Turner, S. S. Hu, J. V. Mosquera, et al., “Single-nucleus Chromatin Accessibility Profiling Highlights Regulatory Mechanisms of Coronary Artery Disease Risk,” Nature Genetics 54 (2022): 804–816.

[328] A. C. Bashore, H. Yan, C. Xue, et al., “High-Dimensional Single-Cell Multimodal Landscape of Human Carotid Atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology 44 (2024): 930–945.

[329] M. Bartosovic, M. Kabbe, and G. Castelo-Branco, “Single-cell CUT&Tag Profiles Histone Modifications and Transcription Factors in Complex Tissues,” Nature Biotechnology 39 (2021): 825–835.

[330] S. J. Wu, S. N. Furlan, A. B. Mihalas, et al., “Single-cell CUT&Tag Analysis of Chromatin Modifications in Differentiation and Tumor Progression,” Nature Biotechnology 39 (2021): 819–824.

[331] B. Zhang, A. Srivastava, E. Mimitou, et al., “Characterizing Cellular Heterogeneity in Chromatin state With scCUT&Tag-pro,” Nature Biotechnology 40 (2022): 1220–1230.

[332] H. Xiong, Y. Luo, Q. Wang, X. Yu, and A. He, “Single-cell Joint Detection of Chromatin Occupancy and Transcriptome Enables Higher-dimensional Epigenomic Reconstructions,” Nature Methods 18 (2021): 652–660.

[333] C. Zhu, Y. Zhang, Y. E. Li, J. Lucero, M. M. Behrens, and B. Ren, “Joint Profiling of Histone Modifications and Transcriptome in Single Cells From Mouse Brain,” Nature Methods 18 (2021): 283–292.

[334] Y. Xie, C. Zhu, Z. Wang, et al., “Droplet-based Single-cell Joint Profiling of Histone Modifications and Transcriptomes,” Nature Structural & Molecular Biology 30 (2023): 1428–1433.

[335] M. Liu, Y. Yue, X. Chen, et al., “Genome-coverage Single-cell Histone Modifications for Embryo Lineage Tracing,” Nature 640 (2025): 828–839.

[336] C. Geisenberger, J. van den Berg, V. van Batenburg, et al., “Single-cell Multi-omic Detection of DNA Methylation and Histone Modifications Reconstructs the Dynamics of Epigenomic Maintenance,” Nature Methods 22 (2025): 2042–2051.

[337] F. Raimundo, P. Prompsy, J. P. Vert, and C. Vallot, “A Benchmark of Computational Pipelines for Single-cell Histone Modification Data,” Genome Biology 24 (2023): 143.

[338] Y. Deng, M. Bartosovic, S. Ma, et al., “Spatial Profiling of Chromatin Accessibility in Mouse and human Tissues,” Nature 609 (2022): 375–383.

[339] C. Kuppe, R. O. Ramirez Flores, Z. Li, et al., “Spatial Multi-omic Map of human Myocardial Infarction,” Nature 608 (2022): 766–777.

[340] J. Sun, P. Singh, A. Shami, et al., “Spatial Transcriptional Mapping Reveals Site-Specific Pathways Underlying Human Atherosclerotic Plaque Rupture,” Journal of the American College of Cardiology 81 (2023): 2213–2227.

[341] M. G. Gastanadui, C. Margaroli, S. Litovsky, et al., “Spatial Transcriptomic Approach to Understanding Coronary Atherosclerotic Plaque Stability,” Arteriosclerosis, Thrombosis, and Vascular Biology 44 (2024): e264–e276.

[342] E. Llorens-Bobadilla, M. Zamboni, M. Marklund, et al., “Solid-phase Capture and Profiling of Open Chromatin by Spatial ATAC,” Nature Biotechnology 41 (2023): 1085–1088.

[343] C. A. Thornton, R. M. Mulqueen, K. A. Torkenczy, et al., “Spatially Mapped Single-cell Chromatin Accessibility,” Nature Communications 12 (2021): 1274.

[344] Y. Deng, M. Bartosovic, P. Kukanja, et al., “Spatial-CUT&Tag: Spatially Resolved Chromatin Modification Profiling at the Cellular Level,” Science 375 (2022): 681–686.

[345] D. Zhang, Y. Deng, P. Kukanja, et al., “Spatial Epigenome-transcriptome co-profiling of Mammalian Tissues,” Nature 616 (2023): 113–122.

[346] A. J. C. Russell, J. A. Weir, N. M. Nadaf, et al., “Slide-tags Enables Single-nucleus Barcoding for Multimodal Spatial Genomics,” Nature 625 (2024): 101–109.

[347] K. Kanemaru, J. Cranley, D. Muraro, et al., “Spatially Resolved Multiomics of human Cardiac Niches,” Nature 619 (2023): 801–810.

[348] P. Guo, L. Mao, Y. Chen, et al., “Multiplexed Spatial Mapping of Chromatin Features, Transcriptome and Proteins in Tissues,” Nature Methods 22 (2025): 520–529.

[349] P. Kiessling and C. Kuppe, “Spatial Multi-omics: Novel Tools to Study the Complexity of Cardiovascular Diseases,” Genome Medicine 16 (2024): 14.

[350] Y. Xia, A. Brewer, and J. T. Bell, “DNA Methylation Signatures of Incident Coronary Heart Disease: Findings From Epigenome-wide Association Studies,” Clinical Epigenetics 13 (2021): 186.

[351] R. Philibert, T. K. Dogan, S. Knight, et al., “Validation of an Integrated Genetic-Epigenetic Test for the Assessment of Coronary Heart Disease,” Journal of the American Heart Association 12 (2023): e030934.

[352] H. Zemmour, D. Planer, J. Magenheim, et al., “Non-invasive Detection of human Cardiomyocyte Death Using Methylation Patterns of Circulating DNA,” Nature Communications 9 (2018): 1443.

[353] J. Ren, L. Jiang, X. Liu, et al., “Heart-specific DNA Methylation Analysis in Plasma for the Investigation of Myocardial Damage,” Journal of Translational Medicine 20 (2022): 36.

[354] R. R. C. Cuadrat, A. Kratzer, H. G. Arnal, et al., “Cardiovascular Disease Biomarkers Derived From Circulating Cell-free DNA Methylation,” NAR Genomics and Bioinformatics 5 (2023): lqad061.

[355] D. K. Tsoneva, D. Buzova, S. D. Bianco, et al., “Histone H2A: A Promising Diagnostic Marker in Heart Failure With Reduced versus Preserved Ejection Fraction,” Molecular and Cellular Biochemistry 480 (2025): 4343–4354.

[356] R. Sadeh, I. Sharkia, G. Fialkoff, et al., “ChIP-seq of Plasma Cell-free Nucleosomes Identifies Gene Expression Programs of the Cells of Origin,” Nature Biotechnology 39 (2021): 586–598.

[357] M. K. Jang, T. E. Markowitz, T. E. Andargie, Z. Apalara, S. Kuhn, and S. Agbor-Enoh, “Cell-free Chromatin Immunoprecipitation to Detect Molecular Pathways in Heart Transplantation,” Life Sci Alliance 6 (2023): e202302003.

[358] L. T. Cooper, K. L. Baughman, A. M. Feldman, et al., “The Role of Endomyocardial Biopsy in the Management of Cardiovascular Disease: A Scientific Statement From the American Heart Association, the American College of Cardiology, and the European Society of Cardiology,” Circulation 116 (2007): 2216–2233.

[359] M. H. Shah, P. Binkley, K. Chan, et al., “Cardiotoxicity of Histone Deacetylase Inhibitor Depsipeptide in Patients With Metastatic Neuroendocrine Tumors,” Clinical Cancer Research 12 (2006): 3997–4003.

[360] C. Huang, W. Huang, L. Zhang, et al., “Targeting Peptide, Fluorescent Reagent Modified Magnetic Liposomes Coated With Rapamycin Target Early Atherosclerotic Plaque and Therapy,” Pharmaceutics 14 (2022): 1083.

[361] C. D. Sago, M. P. Lokugamage, K. Paunovska, et al., “High-throughput in Vivo Screen of Functional mRNA Delivery Identifies Nanoparticles for Endothelial Cell Gene Editing,” Proceedings of the National Academy of Sciences of the United States of America 115 (2018): E9944–e9952.

[362] H. Y. Wey, T. M. Gilbert, N. R. Zürcher, et al., “Insights Into Neuroepigenetics Through human Histone Deacetylase PET Imaging,” Science Translational Medicine 8 (2016): 351ra106.

[363] H. Y. Wey, C. Wang, F. A. Schroeder, J. Logan, J. C. Price, and J. M. Hooker, “Kinetic Analysis and Quantification of [¹¹C]Martinostat for in Vivo HDAC Imaging of the Brain,” Acs Chemical Neuroscience 6 (2015): 708–715.

[364] S. Ørn, C. Manhenke, O. J. Greve, et al., “Microvascular Obstruction Is a Major Determinant of Infarct Healing and Subsequent Left Ventricular Remodelling Following Primary Percutaneous Coronary Intervention,” European Heart Journal 30 (2009): 1978–1985.

[365] A. Borlotti, M. Jerosch-Herold, D. Liu, et al., “Acute Microvascular Impairment Post-Reperfused STEMI Is Reversible and Has Additional Clinical Predictive Value: A CMR OxAMI Study,” JACC Cardiovasc Imaging 12 (2019): 1783–1793.

[366] H. Zukerman, M. Khoury, Y. Shammay, J. Sznitman, N. Lotan, and N. Korin, “Targeting Functionalized Nanoparticles to Activated Endothelial Cells Under High Wall Shear Stress,” Bioengineering & Translational Medicine 5 (2020): e10151.

[367] K. Khodabandehlou, J. J. Masehi-Lano, C. Poon, J. Wang, and E. J. Chung, “Targeting Cell Adhesion Molecules With Nanoparticles Using in Vivo and Flow-based in Vitro Models of Atherosclerosis,” Experimental Biology and Medicine (Maywood, NJ) 242 (2017): 799–812.

[368] W. Chen, M. Schilperoort, Y. Cao, J. Shi, I. Tabas, and W. Tao, “Macrophage-targeted Nanomedicine for the Diagnosis and Treatment of Atherosclerosis,” Nature Reviews Cardiology 19 (2022): 228–249.

[369] R. Castro, J. H. Adair, A. M. Mastro, T. Neuberger, and G. L. Matters, “VCAM-1-targeted Nanoparticles to Diagnose, Monitor and Treat Atherosclerosis,” Nanomedicine (London) 19 (2024): 723–735.

[370] K. Inagaki, S. Fuess, T. A. Storm, et al., “Robust Systemic Transduction With AAV9 Vectors in Mice: Efficient Global Cardiac Gene Transfer Superior to That of AAV8,” Molecular Therapy 14 (2006): 45–53.

[371] Y. Kim, A. P. Landstrom, S. H. Shah, J. C. Wu, and C. E. Seidman, “Gene Therapy in Cardiovascular Disease: Recent Advances and Future Directions in Science: A Science Advisory from the American Heart Association,” Circulation 150 (2024): e471–e480.

[372] L. Rode, C. Bär, S. Groß, et al., “AAV Capsid Engineering Identified Two Novel Variants With Improved in Vivo Tropism for Cardiomyocytes,” Molecular Therapy 30 (2022): 3601–3618.

[373] M. J. W. Evers, W. Du, Q. Yang, et al., “Delivery of Modified mRNA to Damaged Myocardium by Systemic Administration of Lipid Nanoparticles,” Journal of Controlled Release 343 (2022): 207–216.

[374] Y. Ren, B. Zhao, L. Lv, et al., “Non-coding RNAs in Heart Failure: Epigenetic Regulatory Mechanisms and Therapeutic Potential,” Frontiers in Genetics 16 (2025): 1677797.

[375] M. Békés, D. R. Langley, and C. M. Crews, “PROTAC Targeted Protein Degraders: The Past Is Prologue,” Nature Reviews Drug Discovery 21 (2022): 181–200.

[376] D. Chirnomas, K. R. Hornberger, and C. M. Crews, “Protein Degraders Enter the Clinic—a New Approach to Cancer Therapy,” Nature Reviews Clinical oncology 20 (2023): 265–278.

[377] M. Kabir, X. Yu, H. Kaniskan, and J. Jin, “Chemically Induced Degradation of Epigenetic Targets,” Chemical Society Reviews 52 (2023): 4313–4342.

[378] M. Alexanian, P. F. Przytycki, R. Micheletti, et al., “A Transcriptional Switch Governs Fibroblast Activation in Heart Disease,” Nature 595 (2021): 438–443.

[379] V. Tadić, G. Josipović, V. Zoldoš, and A. Vojta, “CRISPR/Cas9-based Epigenome Editing: An Overview of dCas9-based Tools With Special Emphasis on off-target Activity,” Methods (San Diego, California) 164–165 (2019): 109–119.

[380] W. D. Pei, Y. Zhang, T. L. Yin, and Y. Yu, “Epigenome Editing by CRISPR/Cas9 in Clinical Settings: Possibilities and Challenges,” Briefings in Functional Genomics 19 (2020): 215–228.

[381] W. Yao, X. Hu, and X. Wang, “Crossing Epigenetic Frontiers: The Intersection of Novel Histone Modifications and Diseases,” Signal Transduction and Targeted Therapy 9 (2024): 232.

[382] L. Di Venanzio, N. Atzemian, B. Y. Weber, et al., “Pharmacologic and Lifestyle Interventions to Modulate the Epigenome in Heart Failure,” Heart Failure Clinics 22 (2026): 45–56.

[383] O. Martínez-Iglesias, V. Naidoo, I. Carrera, L. Corzo, and R. Cacabelos, “Natural Bioproducts With Epigenetic Properties for Treating Cardiovascular Disorders,” Genes (Basel) 16 (2025): 566.

[384] G. Tai, R. Liu, T. Lin, J. Yang, X. Li, and M. Xu, “Intervention of Natural Products Targeting Novel Mechanisms After Myocardial Infarction,” Chinese Journal of Natural Medicines 23 (2025): 658–672.

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