Epigenetic regulation of cardiac physiology and pathophysiology: biological sex matters

Abstract

Cardiovascular disease (CVD) is the leading cause of global morbidity and mortality, with epigenetic mechanisms playing a pivotal role in its pathogenesis. This review synthesizes current evidence on sex-specific epigenetic regulation in cardiac health and disease, highlighting DNA methylation, histone modifications, and non-coding RNAs as key mediators. Epigenetic processes govern cardiac development, remodeling, and responses to injury, with sex chromosomes, sex hormones, and environmental factors contributing to dimorphic patterns. Developmental programming establishes early sex biases in chromatin architecture while aging and clonal hematopoiesis amplify these differences via mutations in epigenetic modulators. Therapeutic strategies targeting epigenetic regulators hold promise but require sex-tailored approaches to optimize efficacy and minimize off-target effects. This review underscores the critical need for sex-stratified research to advance precision medicine for CVD.

Keywords

Epigenetics / histones / methylation / cardiovascular disease / biological sex

References

[1] Mensah GA,Murray CJL.Global Burden of Cardiovascular Diseases and Risks CollaboratorsGlobal burden of cardiovascular diseases and risks, 1990-2022.J Am Coll Cardiol2023;82:2350-473 PMCID:PMC7615984

[2] Zhang Y,Connolly D.The use of apabetalone in reducing cardiovascular outcomes, based on the current evidence and trials.Eur Cardiol2025;20:e04 PMCID:PMC11934121

[3] Desiderio A,Campitelli M.DNA methylation in cardiovascular disease and heart failure: novel prediction models?.Clin Epigenet2024;16:115 PMCID:PMC11342679

[4] Ardiana M,Zuhra Z,Surya Erlangga Rurus ME.Non-coding RNA therapeutics in cardiovascular diseases and risk factors: systematic review.Noncoding RNA Res2023;8:487-506 PMCID:PMC10362275

[5] Martin TG.Hearts apart: sex differences in cardiac remodeling in health and disease.J Clin Invest2024;134

[6] Reue K.Illuminating the mechanisms underlying sex differences in cardiovascular disease.Circ Res2022;130:1747-62 PMCID:PMC9202078

[7] Shpargel KB,Yokoyama S.UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development.PLoS Genet2012;8:e1002964 PMCID:PMC3459986

[8] Pepin ME,Crossman DK.Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in human ischemic heart failure.Lab Invest2019;99:371-86 PMCID:PMC6515060

[9] Chlamydas S,Strepkos D.Epigenetic mechanisms regulate sex-specific bias in disease manifestations.J Mol Med2022;100:1111-23 PMCID:PMC9244100

[10] Liu R,Yu H,Abbas MN.Methylation across the central dogma in health and diseases: new therapeutic strategies.Signal Transduct Target Ther2023;8:310 PMCID:PMC10449936

[11] Ho JSY,Khong PL,Sia CH.Epigenetics in heart failure.Int J Mol Sci2024;25:12010 PMCID:PMC11593553

[12] Chen Y,Li Y.Chromatin accessibility: biological functions, molecular mechanisms and therapeutic application.Signal Transduct Target Ther2024;9:340 PMCID:PMC11615378

[13] Huang H,Garcia BA.Quantitative proteomic analysis of histone modifications.Chem Rev2015;115:2376-418 PMCID:PMC4502928

[14] Kostova T,Batalov Z,Sarafian V.Recent insights into the role of DNA methylation and histone modifications in systemic sclerosis: a scoping review.Diagnostics2024;14:652 PMCID:PMC10969595

[15] Kujirai T,Sekine SI.Structural transition of the nucleosome during transcription elongation.Cells2023;12:1388 PMCID:PMC10216454

[16] Goldberg AD,Noh KM.Distinct factors control histone variant H3.3 localization at specific genomic regions.Cell2010;140:678-91 PMCID:PMC2885838

[17] Hyun K,Park K.Writing, erasing and reading histone lysine methylations.Exp Mol Med2017;49:e324 PMCID:PMC6130214

[18] Preissl S,Ren B.Characterizing cis-regulatory elements using single-cell epigenomics.Nat Rev Genet2023;24:21-43 PMCID:PMC9771884

[19] Bernstein BE,Erlich RL.Methylation of histone H3 Lys 4 in coding regions of active genes.Proc Natl Acad Sci USA2002;99:8695-700 PMCID:PMC124361

[20] Millán-Zambrano G,Bannister AJ.Histone post-translational modifications - cause and consequence of genome function.Nat Rev Genet2022;23:563-80

[21] Wiles ET.H3K27 methylation: a promiscuous repressive chromatin mark.Curr Opin Genet Dev2017;43:31-7 PMCID:PMC5447479

[22] Tie F,Stratton CA.CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing.Development2009;136:3131-41 PMCID:PMC2730368

[23] Roudier F,Bérard C.Integrative epigenomic mapping defines four main chromatin states in Arabidopsis.EMBO J2011;30:1928-38 PMCID:PMC3098477

[24] Yan K,Li P.The role of post-translational modifications in cardiac hypertrophy.J Cell Mol Med2019;23:3795-807 PMCID:PMC6533522

[25] Stastna M.Post-translational modifications of proteins in cardiovascular diseases examined by proteomic approaches.FEBS J2025;292:28-46 PMCID:PMC11705224

[26] Cheng X,Zhao Y.Research progress on post-translational modification of proteins and cardiovascular diseases.Cell Death Discov2023;9:275 PMCID:PMC10382489

[27] Lee A,Gorski PA,Kho C.Post-translational modifications in heart failure: small changes, big impact.Heart Lung Circ2016;25:319-24 PMCID:PMC4775300

[28] Funamoto M,Tsuchiya K.Roles of histone acetylation sites in cardiac hypertrophy and heart failure.Front Cardiovasc Med2023;10:1133611 PMCID:PMC10050342

[29] Wang Y,Liu Y.Dysregulation of histone acetyltransferases and deacetylases in cardiovascular diseases.Oxid Med Cell Longev2014;2014:641979 PMCID:PMC3945289

[30] Zhou W,Tian J.Acetylation of H3K4, H3K9, and H3K27 mediated by p300 regulates the expression of GATA4 in cardiocytes.Genes Dis2019;6:318-25 PMCID:PMC6997570

[31] Sunagawa Y,Wada H,Morimoto T.[Functional analysis of GATA4 complex, a cardiac hypertrophy-response transcriptional factor, using a proteomics approach].Yakugaku Zasshi2016;136:151-6

[32] Morimoto T,Kawamura T.The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats.J Clin Invest2008;118:868-78

[33] Smith JD.New role for histone deacetylase 9 in atherosclerosis and inflammation.Arterioscler Thromb Vasc Biol2014;34:1798-9 PMCID:PMC4143375

[34] Chen X,Fu W.Histone deacetylases (HDACs) and atherosclerosis: a mechanistic and pharmacological review.Front Cell Dev Biol2020;8:581015 PMCID:PMC7688915

[35] Keller MA.Acetyltransferase in cardiovascular disease and aging.J Cardiovasc Aging2024;4:26 PMCID:PMC11827898

[36] Kouzarides T.Chromatin modifications and their function.Cell2007;128:693-705

[37] Martin C.The diverse functions of histone lysine methylation.Nat Rev Mol Cell Biol2005;6:838-49

[38] Hickenlooper SM,Szulik MW.Histone H4K20 trimethylation is decreased in murine models of heart disease.ACS Omega2022;7:30710-9 PMCID:PMC9453978

[39] Szulik MW,Walsh M.SMYD1a protects the heart from ischemic injury by regulating OPA1-mediated cristae remodeling and supercomplex formation.Basic Res Cardiol2023;118:20 PMCID:PMC10203008

[40] Schiano C,Grimaldi V,De Pascale MR.Epigenetic-related therapeutic challenges in cardiovascular disease.Trends Pharmacol Sci2015;36:226-35

[41] Pandya K,Bultman S.Reversible epigenetic modifications of the two cardiac myosin heavy chain genes during changes in expression.Gene Expr2010;15:51-9 PMCID:PMC3243912

[42] Thienpont B,Robinson EL.The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy.J Clin Invest2017;127:335-48

[43] Chen F,Wang H.Histone lysine methyltransferase SETD2 regulates coronary vascular development in embryonic mouse hearts.Front Cell Dev Biol2021;9:651655 PMCID:PMC8063616

[44] Zhu JY,Han Z.The roles of histone lysine methyltransferases in heart development and disease.J Cardiovasc Dev Dis2023;10:305 PMCID:PMC10380575

[45] Yi X,Wu XL,Jiang XJ.Histone methylation and oxidative stress in cardiovascular diseases.Oxid Med Cell Longev2022;2022:6023710 PMCID:PMC8942669

[46] Lau PNI.Handbook of cell signaling, 2nd edition. Academic Press; 2010. pp. 2399-408.

[47] Zheng M,Min C,Cho DI.β-arrestin2 plays permissive roles in the inhibitory activities of RGS9-2 on G protein-coupled receptors by maintaining RGS9-2 in the open conformation.Mol Cell Biol2011;31:4887-901

[48] Awad S,Marashly Q.Control of histone H3 phosphorylation by CaMKIIδ in response to haemodynamic cardiac stress.J Pathol2015;235:606-18 PMCID:PMC4383650

[49] Wang H,Erdjument-Bromage H.Role of histone H2A ubiquitination in Polycomb silencing.Nature2004;431:873-8

[50] Bandyopadhyay T,Parua PK.Histone H2B monoubiquitylation regulates elongation-to-termination transition in RNA polymerase II transcription.Commun Biol2025;8:1781 PMCID:PMC12714710

[51] Zhao D,Li J.Targeting E3 ubiquitin ligase WWP1 prevents cardiac hypertrophy through destabilizing DVL2 via inhibition of K27-linked ubiquitination.Circulation2021;144:694-711

[52] Nomura S,Fujita T.Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure.Nat Commun2018;9:4435 PMCID:PMC6207673

[53] Gillette TG.Readers, writers, and erasers: chromatin as the whiteboard of heart disease.Circ Res2015;116:1245-53

[54] Wang Z,Zhao TC.Histone deacetylases in modulating cardiac disease and their clinical translational and therapeutic implications.Exp Biol Med2021;246:213-25 PMCID:PMC7871120

[55] Kulthinee S,Zhuang S,Zhao TC.Critical functions of histone deacetylases (HDACs) in modulating inflammation associated with cardiovascular diseases.Pathophysiology2022;29:471-85 PMCID:PMC9397025

[56] Rosales W,García J,Lizcano F.Role of histone demethylases in cardiomyocytes induced to hypertrophy.Biomed Res Int2016;2016:2634976 PMCID:PMC5046009

[57] Cao DJ,Battiprolu PK.Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy.Proc Natl Acad Sci USA2011;108:4123-8 PMCID:PMC3053983

[58] Gillette TG.HDAC inhibition in the heart: erasing hidden fibrosis.Circulation2021;143:1891-3 PMCID:PMC8162936

[59] Zhang QJ.Histone methylations in heart development, congenital and adult heart diseases.Epigenomics2015;7:321-30 PMCID:PMC4451103

[60] Ng SB,Buckingham KJ.Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome.Nat Genet2010;42:790-3 PMCID:PMC2930028

[61] Nguyen AT,Neppl RL.DOT1L regulates dystrophin expression and is critical for cardiac function.Genes Dev2011;25:263-74 PMCID:PMC3034901

[62] Szulik MW,Bakhtina A.Transcriptional regulation by methyltransferases and their role in the heart: highlighting novel emerging functionality.Am J Physiol Heart Circ Physiol2020;319:H847-65 PMCID:PMC7654657

[63] Tang Y,Hong YZ.Expression profiles of histone lysine demethylases during cardiomyocyte differentiation of mouse embryonic stem cells.Acta Pharmacol Sin2014;35:899-906 PMCID:PMC4088288

[64] Van der Meulen J, Speleman F, Van Vlierberghe P. The H3K27me3 demethylase UTX in normal development and disease.Epigenetics2014;9:658-68 PMCID:PMC4063824

[65] Link JC,Chen X.X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity.J Clin Invest2020;130:5688-702

[66] Peeters S,Korecki AJ.Escape from X-chromosome inactivation at KDM5C is driven by promoter-proximal DNA elements and enhanced by domain context.Hum Mol Genet2025;34:978-89 PMCID:PMC12085780

[67] Horitani K,Arai Y.Disruption of the Uty epigenetic regulator locus in hematopoietic cells phenocopies the profibrotic attributes of Y chromosome loss in heart failure.Nat Cardiovasc Res2024;3:343-55 PMCID:PMC11343478

[68] Klattenhoff CA,Surface LE.Braveheart, a long noncoding RNA required for cardiovascular lineage commitment.Cell2013;152:570-83 PMCID:PMC3563769

[69] Han P,Lin CH.A long noncoding RNA protects the heart from pathological hypertrophy.Nature2014;514:102-6 PMCID:PMC4184960

[70] Queirós AM,Fliegner D.Sex- and estrogen-dependent regulation of a miRNA network in the healthy and hypertrophied heart.Int J Cardiol2013;169:331-8

[71] Goodale T,Petak S.Testosterone and the heart.Methodist Debakey Cardiovasc J2017;13:68-72 PMCID:PMC5512682

[72] Thej C.Epigenetic regulation of sex dimorphism in cardiovascular health.Can J Physiol Pharmacol2024;102:498-510 PMCID:PMC11789622

[73] Svoboda LK,Jones TR,Sartor MA.Sex-specific alterations in cardiac DNA methylation in adult mice by perinatal lead exposure.Int J Environ Res Public Health2021;18:577 PMCID:PMC7826866

[74] Wang K,Svoboda LK.Tissue- and sex-specific DNA methylation changes in mice perinatally exposed to lead (Pb).Front Genet2020;11:840 PMCID:PMC7472839

[75] Bridges J,Rosa-Garrido M.Gender-specific genetic and epigenetic signatures in cardiovascular disease.Front Cardiovasc Med2024;11:1355980 PMCID:PMC10962446

[76] Talens RP,Trompet S.Hypermethylation at loci sensitive to the prenatal environment is associated with increased incidence of myocardial infarction.Int J Epidemiol2012;41:106-15 PMCID:PMC3663184

[77] Ferreira C,Ferreira R.Sexual dimorphism in cardiac remodeling: the molecular mechanisms ruled by sex hormones in the heart.J Mol Med2022;100:245-67

[78] Hartman RJG,den Ruijter HM.Sex differences in cardiovascular epigenetics-a systematic review.Biol Sex Differ2018;9:19 PMCID:PMC5966883

[79] Deegan DF,Engel N.Sexual dimorphism of the heart: genetics, epigenetics, and development.Front Cardiovasc Med2021;8:668252 PMCID:PMC8189176

[80] Regitz-Zagrosek V.Mechanistic pathways of sex differences in cardiovascular disease.Physiol Rev2017;97:1-37

[81] Czubryt MP,Fishman GI.Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha ) and mitochondrial function by MEF2 and HDAC5.Proc Natl Acad Sci USA2003;100:1711-6 PMCID:PMC149898

[82] Pan B,Liu L.Epigallocatechin gallate reverses cTnI-low expression-induced age-related heart diastolic dysfunction through histone acetylation modification.J Cell Mol Med2017;21:2481-90 PMCID:PMC5618683

[83] Kumar P.Abstract 006: age and sex differentially regulate epigenetic mechanisms in the heart.Hypertension2023;80:A006

[84] Garcia-Ojalvo J.On time: developmental timing within and across species.Development2023;150:dev201045

[85] Li Y,Deng S.The molecular mechanisms of cardiac development and related diseases.Signal Transduct Target Ther2024;9:368 PMCID:PMC11666744

[86] Pashmforoush M,Chen H.Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block.Cell2004;117:373-86

[87] Bruneau BG,Schmitt JP.A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease.Cell2001;106:709-21

[88] Fang X,Wang-Hu J.Knockdown of DNA methyltransferase 3a alters gene expression and inhibits function of embryonic cardiomyocytes.FASEB J2016;30:3238-55

[89] Gilsbach R,Grüning BA.Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease.Nat Commun2014;5:5288 PMCID:PMC4220495

[90] Li X,Pastor WA.Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling.Proc Natl Acad Sci USA2016;113:E8267-76 PMCID:PMC5187696

[91] Wang Y,Yura Y.Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction.JCI Insight2020;5:135204 PMCID:PMC7213793

[92] Akerberg BN,VanDusen NJ.A reference map of murine cardiac transcription factor chromatin occupancy identifies dynamic and conserved enhancers.Nat Commun2019;10:4907 PMCID:PMC6817842

[93] Papait R,Kunderfranco P.Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy.Proc Natl Acad Sci USA2013;110:20164-9 PMCID:PMC3864351

[94] Delgado-Olguín P,Li X.Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis.Nat Genet2012;44:343-7 PMCID:PMC3288669

[95] Schwaemmle H,Lykoskoufis NMR,Hainard A.CRISPR screen decodes SWI/SNF chromatin remodeling complex assembly.Nat Commun2025;16:5011 PMCID:PMC12125367

[96] Ghosh AK.p300 in cardiac development and accelerated cardiac aging.Aging Dis2020;11:916-26 PMCID:PMC7390535

[97] Wang G,Wang X.Polycomb repressive complex 2 controls cardiac cell fate decision via interacting with RNA: promiscuously or well-ordered.Front Genet2022;13:1011228 PMCID:PMC9614146

[98] Lei I,Sham MH.SWI/SNF protein component BAF250a regulates cardiac progenitor cell differentiation by modulating chromatin accessibility during second heart field development.J Biol Chem2012;287:24255-62 PMCID:PMC3397851

[99] Fudenberg G,Lu C,Abdennur N.Formation of chromosomal domains by loop extrusion.Cell Rep2016;15:2038-49 PMCID:PMC4889513

[100] Andreu MJ,Portela M.Establishment of 3D chromatin structure after fertilization and the metabolic switch at the morula-to-blastocyst transition require CTCF.Cell Rep2022;41:111501

[101] Gomez-Velazquez M,Lechuga-Vieco AV.CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart.PLoS Genet2017;13:e1006985 PMCID:PMC5591014

[102] Ren H,Zhang J.CTCF point mutation at R567 disrupts mouse heart development via 3D genome rearrangement and transcription dysregulation.Cell Prolif2025;58:e13783 PMCID:PMC11969252

[103] Mills JA,Kaur M.NIPBL^+/- haploinsufficiency reveals a constellation of transcriptome disruptions in the pluripotent and cardiac states.Sci Rep2018;8:1056 PMCID:PMC5773608

[104] Mfarej MG,Sanchez AC,Iovine MK.Cohesin: an emerging master regulator at the heart of cardiac development.Mol Biol Cell2023;34:rs2 PMCID:PMC10162415

[105] Schuster K,Meier M.A neural crest origin for cohesinopathy heart defects.Hum Mol Genet2015;24:7005-16 PMCID:PMC4654055

[106] Zhang B,Zhang Z.SMC3 contributes to heart development by regulating super-enhancer associated genes.Exp Mol Med2024;56:1826-42 PMCID:PMC11372143

[107] Bertero A.Three-dimensional chromatin organization in cardiac development and disease.J Mol Cell Cardiol2021;151:89-105 PMCID:PMC11056610

[108] Matthews BJ.Impact of 3D genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver.Epigenet Chromatin2020;13:30

[109] Fang H,Berletch JB.X inactivation and escape: epigenetic and structural features.Front Cell Dev Biol2019;7:219 PMCID:PMC6779695

[110] Fleurie A,Manuse S.MapZ marks the division sites and positions FtsZ rings in Streptococcus pneumoniae.Nature2014;516:259-62 PMCID:PMC4268495

[111] Oda T,Aihara T,Narita A.Erratum: the nature of the globular- to fibrous-actin transition.Nature2009;461:550

[112] Hanssen LLP,Oudelaar AM.Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo.Nat Cell Biol2017;19:952-61 PMCID:PMC5540176

[113] Deegan DF.Sexual dimorphism in the age of genomics: how, when, where.Front Cell Dev Biol2019;7:186 PMCID:PMC6743004

[114] McClain AK,Zoldan J.Sex in cardiovascular disease: why this biological variable should be considered in in vitro models.Sci Adv2024;10:eadn3510 PMCID:PMC11086622

[115] Trexler CL,Jeong MY,Leinwand LA.Transcriptome and functional profile of cardiac myocytes is influenced by biological sex.Circ Cardiovasc Genet2017;10:e001770 PMCID:PMC5679409

[116] D'Antonio-Chronowska A,Young Greenwald WW.Association of human iPSC gene signatures and X chromosome dosage with two distinct cardiac differentiation trajectories.Stem Cell Reports2019;13:924-38 PMCID:PMC6895695

[117] Bermejo-Alvarez P,Rath D,Gutierrez-Adan A.Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts.Proc Natl Acad Sci USA2010;107:3394-9 PMCID:PMC2840439

[118] Wijchers PJ,Panousopoulou E.Sexual dimorphism in mammalian autosomal gene regulation is determined not only by Sry but by sex chromosome complement as well.Dev Cell2010;19:477-84

[119] Wrenzycki C,Herrmann D,Korsawe K.In vitro production and nuclear transfer affect dosage compensation of the X-linked gene transcripts G6PD, PGK, and Xist in preimplantation bovine embryos.Biol Reprod2002;66:127-34

[120] Taylor DM,Ray PF,Winston RM.Quantitative measurement of transcript levels throughout human preimplantation development: analysis of hypoxanthine phosphoribosyl transferase.Mol Hum Reprod2001;7:147-54

[121] Bermejo-Alvarez P,Rath D,Gutierrez-Adan A.Epigenetic differences between male and female bovine blastocysts produced in vitro.Physiol Genomics2008;32:264-72

[122] Bermejo-Alvarez P,Lonergan P.Transcriptional sexual dimorphism during preimplantation embryo development and its consequences for developmental competence and adult health and disease.Reproduction2011;141:563-70

[123] Gebert C,Herrmann D.DNA methylation in the IGF2 intragenic DMR is re-established in a sex-specific manner in bovine blastocysts after somatic cloning.Genomics2009;94:63-9

[124] Deegan DF,Madzo J,Engel N.The developmental origins of sex-biased expression in cardiac development.Biol Sex Differ2019;10:46 PMCID:PMC6727560

[125] Dehingia B,Janowski M.CTCF shapes chromatin structure and gene expression in health and disease.EMBO Rep2022;23:e55146 PMCID:PMC9442299

[126] Fang H,Bonora G.CTCF-mediated insulation and chromatin environment modulate Car5b escape from X inactivation.bioRxiv2023; PMCID:PMC10187265

[127] Arnold AP,Eghbali M,Sandberg K.Sex hormones and sex chromosomes cause sex differences in the development of cardiovascular diseases.Arterioscler Thromb Vasc Biol2017;37:746-56 PMCID:PMC5437981

[128] Wang K,Hu Q.Epigenetic regulation of aging: implications for interventions of aging and diseases.Signal Transduct Target Ther2022;7:374 PMCID:PMC9637765

[129] Duan R,Sun Y.Epigenetic clock: a promising biomarker and practical tool in aging.Ageing Res Rev2022;81:101743

[130] Liang R,Chen J.Epigenetic clocks: beyond biological age, using the past to predict the present and future.Aging Dis2024;16:3520-45

[131] Hägg S.Sex differences in biological aging with a focus on human studies.Elife2021;10:e63425 PMCID:PMC8118651

[132] Liang Y,Kong M.Gender differences in cardiac remodeling induced by a high-fat diet and lifelong, low-dose cadmium exposure.Chem Res Toxicol2019;32:1070-81 PMCID:PMC7060501

[133] Blin G,Mauduit C.Maternal exposure to high-fat diet induces long-term derepressive chromatin marks in the heart.Nutrients2020;12:181 PMCID:PMC7019950

[134] Jaiswal S,Flannick J.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med2014;371:2488-98

[135] Fuster JJ,Zuriaga MA.Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.Science2017;355:842-7

[136] Zink F,Norddahl GL.Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly.Blood2017;130:742-52 PMCID:PMC5553576

[137] Fuster JJ.Somatic mutations and clonal hematopoiesis: unexpected potential new drivers of age-related cardiovascular disease.Circ Res2018;122:523-32 PMCID:PMC5826570

[138] Dorsheimer L,Rasper T.Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure.JAMA Cardiol2019;4:25-33 PMCID:PMC6439691

[139] Yu B,Raffield LM.Supplemental association of clonal hematopoiesis with incident heart failure.J Am Coll Cardiol2021;78:42-52 PMCID:PMC8313294

[140] Jaiswal S,Silver AJ.Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.N Engl J Med2017;377:111-21

[141] Cobo I,Alishala M.Particle uptake by macrophages triggers bifurcated transcriptional pathways that differentially regulate inflammation and lysosomal gene expression.Immunity2025;58:826-42.e8 PMCID:PMC12093573

[142] Cobo I,Chandra Mangalhara K.DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages.Immunity2022;55:1386-401.e10 PMCID:PMC9718507

[143] Díez-Díez M,de la Barrera J.Unidirectional association of clonal hematopoiesis with atherosclerosis development.Nat Med2024;30:2857-66 PMCID:PMC11485253

[144] Iorga A,Moazeni S,Umar S.The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy.Biol Sex Differ2017;8:33 PMCID:PMC5655818

[145] Meng Q,Ji T.Estrogen prevent atherosclerosis by attenuating endothelial cell pyroptosis via activation of estrogen receptor α-mediated autophagy.J Adv Res2021;28:149-64 PMCID:PMC7753237

[146] Rauch PJ,Silver AJ.Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.Nat Cardiovasc Res2023;2:805-18

[147] Murphy AJ,Pioli PA.Estradiol suppresses NF-kappa B activation through coordinated regulation of let-7a and miR-125b in primary human macrophages.J Immunol2010;184:5029-37 PMCID:PMC2882792

[148] Pepin ME,Ha CM.DNA methylation reprograms cardiac metabolic gene expression in end-stage human heart failure.Am J Physiol Heart Circ Physiol2019;317:H674-84 PMCID:PMC6843013

[149] Wong LL,Sepramaniam S.Circulating microRNAs in heart failure with reduced and preserved left ventricular ejection fraction.Eur J Heart Fail2015;17:393-404

[150] Hahn VS,Luo X.Myocardial gene expression signatures in human heart failure with preserved ejection fraction.Circulation2021;143:120-34

[151] van Ommen AMLN, Canto ED, Cramer MJ, Rutten FH, Onland-Moret NC, Ruijter HMD. Diastolic dysfunction and sex-specific progression to HFpEF: current gaps in knowledge and future directions.BMC Med2022;20:496 PMCID:PMC9795723

[152] Rabkin SW.Epigenetics in heart failure: role of DNA methylation in potential pathways leading to heart failure with preserved ejection fraction.Biomedicines2023;11:2815 PMCID:PMC10604152

[153] Watson CJ,Tea I.Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype.Hum Mol Genet2014;23:2176-88

[154] Borlaug BA.Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment.Eur Heart J2011;32:670-9 PMCID:PMC3056204

[155] Sarker H,Toor R.The emerging role of epigenetic mechanisms in the causation of aberrant MMP activity during human pathologies and the use of medicinal drugs.Biomolecules2021;11:578 PMCID:PMC8071227

[156] Zhao X,Ruan X.A deep learning model for early risk prediction of heart failure with preserved ejection fraction by DNA methylation profiles combined with clinical features.Clin Epigenet2022;14:11 PMCID:PMC8772140

[157] Schuermans A,Raffield LM.Clonal hematopoiesis and incident heart failure with preserved ejection fraction.JAMA Netw Open2024;7:e2353244 PMCID:PMC10811556

[158] Pillai VB,Kim G.Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway.J Biol Chem2010;285:3133-44

[159] Watson CJ,O'Connell E.MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure.Eur J Heart Fail2015;17:405-15 PMCID:PMC4418397

[160] Satoh T,Espinosa-Diez C.Metabolic syndrome mediates ROS-miR-193b-NFYA-dependent downregulation of soluble guanylate cyclase and contributes to exercise-induced pulmonary hypertension in heart failure with preserved ejection fraction.Circulation2021;144:615-37 PMCID:PMC8384699

[161] Abbas M.Emerging roles of noncoding RNAs in cardiovascular pathophysiology.Am J Physiol Heart Circ Physiol2025;328:H603-21

[162] Piccoli MT,Viereck J.Inhibition of the cardiac fibroblast-enriched lncRNA Meg3 prevents cardiac fibrosis and diastolic dysfunction.Circ Res2017;121:575-83

[163] Mably JD.Long non-coding RNAs in cardiac hypertrophy and heart failure: functions, mechanisms and clinical prospects.Nat Rev Cardiol2024;21:326-45 PMCID:PMC11031336

[164] Micheletti R,Abraham BJ.The long noncoding RNA Wisper controls cardiac fibrosis and remodeling.Sci Transl Med2017;9:eaai9118 PMCID:PMC5643582

[165] Neumann P,Knau A.The lncRNA GATA6-AS epigenetically regulates endothelial gene expression via interaction with LOXL2.Nat Commun2018;9:237 PMCID:PMC5770451

[166] Hamdani N,Mügge A.Leveraging clinical epigenetics in heart failure with preserved ejection fraction: a call for individualized therapies.Eur Heart J2021;42:1940-58 PMCID:PMC8921660

[167] Witt H,Jaekel J.Sex-specific pathways in early cardiac response to pressure overload in mice.J Mol Med2008;86:1013-24 PMCID:PMC2517094

[168] Murphy E,Fillmore N,Sun J.Sex differences in metabolic cardiomyopathy.Cardiovasc Res2017;113:370-7 PMCID:PMC5852638

[169] Fliegner D,Angelov A,Regitz-Zagrosek V.Sex differences and estrogen effects in cardiac mitochondria in human aortic stenosis and in the mouse heart.Front Endocrinol2023;14:1181044 PMCID:PMC10617023

[170] Tong D,Jiang N.Female sex is protective in a preclinical model of heart failure with preserved ejection fraction.Circulation2019;140:1769-71

[171] Fopiano KA,Patel VS,Bagi Z.Sex-specific molecular drivers of cardiac fibrosis in aging hearts.Geroscience2025;47:5749-61 PMCID:PMC12397039

[172] Pedram A,Narayanan R,McKinsey TA.Estrogen regulates histone deacetylases to prevent cardiac hypertrophy.Mol Biol Cell2013;24:3805-18 PMCID:PMC3861078

[173] Svoboda LK,Goodrich JM.Perinatal lead exposure promotes sex-specific epigenetic programming of disease-relevant pathways in mouse heart.Toxics2023;11:85 PMCID:PMC9860846

[174] Florijn BW,Duijs JMGJ.Sex-specific microRNAs in women with diabetes and left ventricular diastolic dysfunction or HFpEF associate with microvascular injury.Sci Rep2020;10:13945 PMCID:PMC7435264

[175] K N H,Mathiyalagan P.Sex-based mhrt methylation chromatinizes MeCP2 in the heart.iScience2019;17:288-301 PMCID:PMC6639684

[176] Shi Y,Liu J.Clinical implications of plasma galectin-3 in heart failure with preserved ejection fraction: a meta-analysis.Front Cardiovasc Med2022;9:854501 PMCID:PMC9046693

[177] Baccouche BM,Nief C,Natterson-Horowitz B.Galectin-3 is Associated with heart failure incidence: a meta-analysis.Curr Cardiol Rev2023;19:e171122211004 PMCID:PMC10280995

[178] Ma W,Pease N,Disteche CM.Sex-biased and parental allele-specific gene regulation by KDM6A.Biol Sex Differ2022;13:40 PMCID:PMC9308343

[179] Burchfield JS,Hill JA.Pathological ventricular remodeling: mechanisms: part 1 of 2.Circulation2013;128:388-400 PMCID:PMC3801217

[180] Shi Y,Huang S.Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials.Signal Transduct Target Ther2022;7:200 PMCID:PMC9233709

[181] Chandra S,Lacey M,Ehrlich M.Epigenetics and expression of key genes associated with cardiac fibrosis: NLRP3, MMP2, MMP9, CCN2/CTGF and AGT.Epigenomics2021;13:219-34 PMCID:PMC7907962

[182] Guo Z,Zhou Z.Integrative DNA methylome and transcriptome analysis identify potential genes on the influence of dilated cardiomyopathy-associated heart failure.Clin Epigenet2025;17:64 PMCID:PMC12036135

[183] Madsen A,Krause J.An important role for DNMT3A-mediated DNA methylation in cardiomyocyte metabolism and contractility.Circulation2020;142:1562-78

[184] Chapski DJ,Morselli M.Early adaptive chromatin remodeling events precede pathologic phenotypes and are reinforced in the failing heart.J Mol Cell Cardiol2021;160:73-86 PMCID:PMC9181638

[185] Awad S,Little GH.Nuclear CaMKII enhances histone H3 phosphorylation and remodels chromatin during cardiac hypertrophy.Nucleic Acids Res2013;41:7656-72 PMCID:PMC3763528

[186] Wang M,Zhang Y.CBP/p300 and HDAC activities regulate H3K27 acetylation dynamics and zygotic genome activation in mouse preimplantation embryos.EMBO J2022;41:e112012 PMCID:PMC9670200

[187] Han Y,Wang DW.Mechanism of histone deacetylases in cardiac hypertrophy and its therapeutic inhibitors.Front Cardiovasc Med2022;9:931475 PMCID:PMC9360326

[188] Song Z,Yan B.Potential roles of microRNA-1 and microRNA-133 in cardiovascular disease.Rev Cardiovasc Med2020;21:57-64

[189] Micu MA,Scridon A.miRNA-orchestrated fibroinflammatory responses in heart failure with preserved ejection fraction: translational opportunities for precision medicine.Diagnostics2025;15:2286 PMCID:PMC12468781

[190] Boichenko V,Reilly-O'Donnell B.Circulating non-coding RNAs as indicators of fibrosis and heart failure severity.Cells2025;14:553 PMCID:PMC11989213

[191] Lin J,Ma L.KDM6A facilitates Xist upregulation at the onset of X inactivation.Biol Sex Differ2025;16:1 PMCID:PMC11699772

[192] Sen A,Senut MC.Early life lead exposure causes gender-specific changes in the DNA methylation profile of DNA extracted from dried blood spots.Epigenomics2015;7:379-93 PMCID:PMC4501025

[193] van Rooij E,Sutherland LB.Myocyte enhancer factor 2 and class II histone deacetylases control a gender-specific pathway of cardioprotection mediated by the estrogen receptor.Circ Res2010;106:155-65

[194] Karvinen S,Le G.Estradiol deficiency and skeletal muscle apoptosis: possible contribution of microRNAs.Exp Gerontol2021;147:111267 PMCID:PMC9897888

[195] Huo JL,An Q.Myofibroblast deficiency of LSD1 alleviates TAC-induced heart failure.Circ Res2021;129:400-13

[196] Waddell A,Ding H,Liao D.Pharmacological inhibition of CBP/p300 blocks estrogen receptor alpha (ERα) function through suppressing enhancer H3K27 acetylation in luminal breast cancer.Cancers2021;13:2799 PMCID:PMC8200112

[197] Biamonte F,Zolea F.Ferritin heavy subunit enhances apoptosis of non-small cell lung cancer cells through modulation of miR-125b/p53 axis.Cell Death Dis2018;9:1174 PMCID:PMC6281584

[198] Izzo LT.Histone lactylation links metabolism and gene regulation.Nature2019;574:492-3

[199] Crosswhite P.TNFα induces DNA and histone hypomethylation and pulmonary artery smooth muscle cell proliferation partly via excessive superoxide formation.Antioxidants2024;13:677 PMCID:PMC11200563

[200] Zhang Y,Tan L,Shi YG.Understanding the role of ten-eleven translocation family proteins in kidney diseases.Biochem Soc Trans2024;52:2203-14

[201] Zhang X,Xu H,Ma H.Critical roles of m⁶A methylation in cardiovascular diseases.Front Cardiovasc Med2023;10:1187514 PMCID:PMC10235536

[202] Wang H,Jiang X.Emerging mechanisms and implications of m⁶A in CVDs: potential applications of natural products.Front Cardiovasc Med2025;12:1559064 PMCID:PMC12256525

[203] Long H,Ouyang J,Zhao G.Insights into RNA N6-methyladenosine and programmed cell death in atherosclerosis.Mol Med2024;30:137 PMCID:PMC11373444

[204] Di Ferrante N,Angelini P.Ehlers danlos type V (X linked form): a lysyl oxidase deficiency.Birth Defects Orig Artic Ser1975;11:31-7Available from: https://hdl.handle.net/20.500.14716/24586 [accessed 10 Feb 2026].

[205] Leng Y,Lei S.Inhibition of HDAC6 activity alleviates myocardial ischemia/reperfusion injury in diabetic rats: potential role of peroxiredoxin 1 acetylation and redox regulation.Oxid Med Cell Longev2018;2018:9494052 PMCID:PMC6036837

[206] Gottlieb PD,Sims RJ.Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis.Nat Genet2002;31:25-32

[207] Warren JS,Miller MR.Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart.Proc Natl Acad Sci USA2018;115:E7871-80 PMCID:PMC6099878

[208] Wang JX,Li Q.MicroRNA-103/107 regulate programmed necrosis and myocardial ischemia/reperfusion injury through targeting FADD.Circ Res2015;117:352-63

[209] Meng K,Zhu RR.The long noncoding RNA hotair regulates oxidative stress and cardiac myocyte apoptosis during ischemia-reperfusion injury.Oxid Med Cell Longev2020;2020:1645249 PMCID:PMC7091551

[210] Ghafouri-Fard S,Taheri M.Non-coding RNAs participate in the ischemia-reperfusion injury.Biomed Pharmacother2020;129:110419

[211] Bo X,Chen S.Evidence and perspectives on miRNA, circRNA, and lncRNA in myocardial ischemia-reperfusion injury: a bibliometric study.J Cardiothorac Surg2025;20:66 PMCID:PMC11736979

[212] Kessler EL,Vos MA.Sex-specific influence on cardiac structural remodeling and therapy in cardiovascular disease.Biol Sex Differ2019;10:7 PMCID:PMC6360698

[213] Le TY,Mardini M.Role of androgens in sex differences in cardiac damage during myocardial infarction.Endocrinology2014;155:568-75

[214] Yi P,Feng Q.Structure of a biologically active estrogen receptor-coactivator complex on DNA.Mol Cell2015;57:1047-58 PMCID:PMC4369429

[215] Liu J,Zuo S.Dot1L promotes stress-induced cardiac hypertrophy in mice via Tbx6.Circ Res2025;137:496-512

[216] Komar D.Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy.Clin Epigenet2020;12:147 PMCID:PMC7556946

[217] Sheedy FJ.Turning 21: induction of miR-21 as a key switch in the inflammatory response.Front Immunol2015;6:19 PMCID:PMC4310327

[218] Solela G,Zegeye H,Leulseged B.Prevalence, patterns, and determinants of vascular complications of type 2 diabetes in a teaching hospital in Addis Ababa, Ethiopia: a retrospective study.BMC Endocr Disord2024;24:190 PMCID:PMC11409534

[219] Kiselev I,Baulina N.Novel genes involved in hypertrophic cardiomyopathy: data of transcriptome and methylome profiling.Int J Mol Sci2022;23:15280 PMCID:PMC9739701

[220] Duan Q,Anand P.BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure.Sci Transl Med2017;9:eaah5084

[221] Auguste G,Matkovich SJ.BET bromodomain inhibition attenuates cardiac phenotype in myocyte-specific lamin A/C-deficient mice.J Clin Invest2020;130:4740-58

[222] Greco S,Perfetti A.Long noncoding RNA dysregulation in ischemic heart failure.J Transl Med2016;14:183 PMCID:PMC4912721

[223] Xuan L,Zhang Y.Circulating long non-coding RNAs NRON and MHRT as novel predictive biomarkers of heart failure.J Cell Mol Med2017;21:1803-14 PMCID:PMC5571539

[224] Felisbino MB.Epigenetics in cardiac fibrosis: emphasis on inflammation and fibroblast activation.JACC Basic Transl Sci2018;3:704-15 PMCID:PMC6234501

[225] Garmany R,Bos JM.Abstract 17329: histone modifications regulate hypertrophy pathways in obstructive hypertrophic cardiomyopathy.Circulation2023;148:A17329

[226] Ueda K,Adachi Y.Sex differences and regulatory actions of estrogen in cardiovascular system.Front Physiol2021;12:738218 PMCID:PMC8505986

[227] Butters A,Ingles J.Sex differences in hypertrophic cardiomyopathy: interaction with genetics and environment.Curr Heart Fail Rep2021;18:264-73 PMCID:PMC8484093

[228] Jansen M,Hassanzada F.Penetrance and prognosis of MYH7 variant-associated cardiomyopathies: results from a dutch multicenter cohort study.JACC Heart Fail2024;12:134-47

[229] Cibi DM,Shekeran SG.Prdm16 deficiency leads to age-dependent cardiac hypertrophy, adverse remodeling, mitochondrial dysfunction, and heart failure.Cell Rep2020;33:108288

[230] Kühnisch J,Dartsch J.Prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators.Cardiovasc Res2024;119:2902-16 PMCID:PMC10874277

[231] Sun B,Kramer RJ.Nonsense variant PRDM16-Q187X causes impaired myocardial development and TGF-β signaling resulting in noncompaction cardiomyopathy in humans and mice.Circ Heart Fail2023;16:e010351

[232] Arndt AK,Drenckhahn JD.Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.Am J Hum Genet2013;93:67-77

[233] Kramer RJ,Chan A.PRDM16 deletion is associated with sex-dependent cardiomyopathy and cardiac mortality: a translational, multi-institutional cohort study.Circ Genom Precis Med2023;16:390-400

[234] Zhang S,Jiang C.Inhibition of histone demethylase JMJD1C attenuates cardiac hypertrophy and fibrosis induced by angiotensin II.J Recept Signal Transduct Res2020;40:339-47

[235] Yang L,Ma W.Ablation of lncRNA Miat attenuates pathological hypertrophy and heart failure.Theranostics2021;11:7995-8007 PMCID:PMC8315059

[236] Su W,Wu H.The function of LncRNA-H19 in cardiac hypertrophy.Cell Biosci2021;11:153 PMCID:PMC8336097

[237] Lan Y,Pan H.Stage-specific regulation of DNA methylation by TET enzymes during human cardiac differentiation.Cell Rep2021;37:110095 PMCID:PMC11229417

[238] Izquierdo C,Martin-Isla C.Radiomics-based classification of left ventricular non-compaction, hypertrophic cardiomyopathy, and dilated cardiomyopathy in cardiovascular magnetic resonance.Front Cardiovasc Med2021;8:764312 PMCID:PMC8586199

[239] Broome R,Jamieson S.TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions.Cell Rep2021;34:108776 PMCID:PMC7921846

[240] Ang SY,Spencer CI.KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation.Development2016;143:810-21 PMCID:PMC4813342

[241] McKinsey TA,Anene-Nzelu CG.Emerging epigenetic therapies of cardiac fibrosis and remodelling in heart failure: from basic mechanisms to early clinical development.Cardiovasc Res2023;118:3482-98 PMCID:PMC10202443

[242] García-Calzón S,Eichelmann F.Epigenetic biomarkers predict macrovascular events in individuals with type 2 diabetes.Cell Rep Med2025;6:102290 PMCID:PMC12432358

[243] Dhaenens M.Histone clipping: the punctuation in the histone code.EMBO Rep2021;22:e53440 PMCID:PMC8344887

[244] Yoon S.HDAC and HDAC inhibitor: from cancer to cardiovascular diseases.Chonnam Med J2016;52:1-11 PMCID:PMC4742605

[245] Naumenko N,Holappa L,Tuomainen T.PGC-1α deficiency reveals sex-specific links between cardiac energy metabolism and EC-coupling during development of heart failure in mice.Cardiovasc Res2022;118:1520-34 PMCID:PMC9074965

[246] Schuetze KB,Blakeslee WW.Overlapping and divergent actions of structurally distinct histone deacetylase inhibitors in cardiac fibroblasts.J Pharmacol Exp Ther2017;361:140-50 PMCID:PMC5363768

[247] Peng X,Wang Q.Pan-histone deacetylase inhibitor vorinostat suppresses osteoclastic bone resorption through modulation of RANKL-evoked signaling and ameliorates ovariectomy-induced bone loss.Cell Commun Signal2024;22:160 PMCID:PMC10913587

[248] Yoon S,Eom GH.HDAC inhibitors: therapeutic potential in fibrosis-associated human diseases.Int J Mol Sci2019;20:1329 PMCID:PMC6471162

[249] Filippakopoulos P,Picaud S.Selective inhibition of BET bromodomains.Nature2010;468:1067-73 PMCID:PMC3010259

[250] Spiltoir JI,Cavasin MA.BET acetyl-lysine binding proteins control pathological cardiac hypertrophy.J Mol Cell Cardiol2013;63:175-9 PMCID:PMC4089995

[251] Nagarajan S,Alawi M.Bromodomain protein BRD4 is required for estrogen receptor-dependent enhancer activation and gene transcription.Cell Rep2014;8:460-9 PMCID:PMC4747248

[252] Ray KK,Ginsberg HD.Effect of selective BET protein inhibitor apabetalone on cardiovascular outcomes in patients with acute coronary syndrome and diabetes: Rationale, design, and baseline characteristics of the BETonMACE trial.Am Heart J2019;217:72-83

[253] Papait R,Pagiatakis C.Histone methyltransferase G9a is required for cardiomyocyte homeostasis and hypertrophy.Circulation2017;136:1233-46

[254] Cabrera Zapata LE, Cambiasso MJ, Arevalo MA. Epigenetic modifier Kdm6a/Utx controls the specification of hypothalamic neuronal subtypes in a sex-dependent manner.Front Cell Dev Biol2022;10:937875 PMCID:PMC9577230

[255] Huang Y,Zhang M.Nullifying epigenetic writer DOT1L attenuates neointimal hyperplasia.Atherosclerosis2020;308:22-31 PMCID:PMC7503165

[256] Nonaka CKV,Silva KN.Therapeutic miR-21 silencing reduces cardiac fibrosis and modulates inflammatory response in chronic chagas disease.Int J Mol Sci2021;22:3307 PMCID:PMC8036348

[257] Murphy E.Estrogen signaling and cardiovascular disease.Circ Res2011;109:687-96 PMCID:PMC3398381

[258] Tian J,Liang L.Targeting the unique methylation pattern of androgen receptor (AR) promoter in prostate stem/progenitor cells with 5-aza-2'-deoxycytidine (5-AZA) leads to suppressed prostate tumorigenesis.J Biol Chem2012;287:39954-66