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Epigenetics of Aberrant Cardiac Wound Healing

Adam Russell‐Hallinan, Chris J. Watson, John A. Baugh

10.1002/cphy.c170029

Source: Volume 8, Issue 2, April 2018

Published online: March 2018

Full Article on Wiley Online Library



ABSTRACT

Remodeling of cardiac tissue architecture is essential for normal organ development and maintaining homeostasis after injury. Injurious insults to the heart, such as hypertension and myocardial infarction, promote cellular responses including stimulation of resident inflammatory cells, activation of endothelial cells and recruitment of immune cells, hypertrophy of cardiomyocytes, and activation of fibroblasts. The physiological goal of this coordinated cellular response is to repair damaged tissue while maintaining or restoring cardiac contractile function. Persistent uncontrolled inflammation, hypertrophy, and fibrosis in the heart due to hyperactive wound healing are detrimental and impair cardiac performance, facilitating the progression to heart failure. Abnormal changes in gene expression promote acquisition of aberrant cellular phenotypes that drive cardiac remodeling. DNA methylation and histone modifications are epigenetic mechanisms that critically regulate chromatin structure and gene expression, and are essential for normal physiology and development. Increasing clinical and experimental evidence suggests that these epigenetic mechanisms are involved in driving aberrant wound healing and the development of heart failure. While most of our knowledge to date is on the heart as a whole, the precise contribution of DNA methylation and histone modifications in regulating aberrant cardiac remodeling at the cellular level is less defined. Therefore, this overview aims to summarize the role of DNA methylation and histone modifications (acetylation and methylation) in heart failure and to comprehensively dissect the role these mechanisms play in regulating the function of cardiomyocytes, fibroblasts, and immune cells in response to injury. © 2018 American Physiological Society. Compr Physiol 8:451‐491, 2018.

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Figure 1. Figure 1. Schematic overview highlighting epigenetic changes associated with cardiac injury that lead to the acquisition of hyperactive cellular phenotypes in cardiomyocytes, fibroblasts and immune cells, and promote aberrant pathological remodeling in the heart.
Figure 2. Figure 2. Regulation of gene transcription by DNA methylation and demethylation in the promoter region. The addition of a methyl group (‐CH3) to carbon 5 on the cytosine ring (C), is catalysed by the DNA methyltransferase (DNMT) enzymes forming 5‐methylcytosine (5MeC). S‐adenosylmethionine (SAM) is utilized as a methyl donor that is subsequently converted to S‐adenosylhomocysteine (SAH) upon donation. Methyl‐CpG‐binding proteins (MeCP) and methyl‐CpG‐binding domain protein (MBD) proteins are recruited to 5MeC resulting in gene silencing by preventing transcription factor (TF) and binding of RNA polymerase II (RNApolII) binding. Conversely, removal of methylated cytosines can be enzymatically carried out by the ten‐eleven translocation (TET) enzymes, which oxidize 5MeC to 5‐hydroxymethylcytosine (5hMeC). Small molecule inhibitors of DNMT activity prevent 5MeC formation and together these processes promote gene expression by allowing TF and RNApolII to bind to the DNA.
Figure 3. Figure 3. Control of gene expression through regulation of chromatin structure by acetylation and methylation of histone proteins. Formation of heterochromatin structure and repression of gene expression is facilitated by both the removal of acetyl groups from histone tails by histone deacetylases (HDACs) and the actions of histone lysine methyltransferases (HMTs) and demethylases (HDMs) forming repressive histone marks (H3K9, H3K20, H3K27). Conversely, promotion of gene expression and euchromatin structure is carried out by enzymatic addition of acetyl groups by histone acetyltransferases (HATs) and the actions of HMTs and HDMs forming active histone marks (H3K4, H3K26, H3K79). Abbreviations: HMTs, histone methyltransferases; HDMs, histone demethylases; HATs, histone acetyltransferases; HDACs, histone deacetylases; CH3, methyl group. Yellow pentagon: active histone marks, blue pentagon: repressive histone marks, green marks: active acetylation marks.


Figure 1. Schematic overview highlighting epigenetic changes associated with cardiac injury that lead to the acquisition of hyperactive cellular phenotypes in cardiomyocytes, fibroblasts and immune cells, and promote aberrant pathological remodeling in the heart.


Figure 2. Regulation of gene transcription by DNA methylation and demethylation in the promoter region. The addition of a methyl group (‐CH3) to carbon 5 on the cytosine ring (C), is catalysed by the DNA methyltransferase (DNMT) enzymes forming 5‐methylcytosine (5MeC). S‐adenosylmethionine (SAM) is utilized as a methyl donor that is subsequently converted to S‐adenosylhomocysteine (SAH) upon donation. Methyl‐CpG‐binding proteins (MeCP) and methyl‐CpG‐binding domain protein (MBD) proteins are recruited to 5MeC resulting in gene silencing by preventing transcription factor (TF) and binding of RNA polymerase II (RNApolII) binding. Conversely, removal of methylated cytosines can be enzymatically carried out by the ten‐eleven translocation (TET) enzymes, which oxidize 5MeC to 5‐hydroxymethylcytosine (5hMeC). Small molecule inhibitors of DNMT activity prevent 5MeC formation and together these processes promote gene expression by allowing TF and RNApolII to bind to the DNA.


Figure 3. Control of gene expression through regulation of chromatin structure by acetylation and methylation of histone proteins. Formation of heterochromatin structure and repression of gene expression is facilitated by both the removal of acetyl groups from histone tails by histone deacetylases (HDACs) and the actions of histone lysine methyltransferases (HMTs) and demethylases (HDMs) forming repressive histone marks (H3K9, H3K20, H3K27). Conversely, promotion of gene expression and euchromatin structure is carried out by enzymatic addition of acetyl groups by histone acetyltransferases (HATs) and the actions of HMTs and HDMs forming active histone marks (H3K4, H3K26, H3K79). Abbreviations: HMTs, histone methyltransferases; HDMs, histone demethylases; HATs, histone acetyltransferases; HDACs, histone deacetylases; CH3, methyl group. Yellow pentagon: active histone marks, blue pentagon: repressive histone marks, green marks: active acetylation marks.
References
 1.Adcock IM. HDAC inhibitors as anti‐inflammatory agents. Brit J Pharmacol 150: 829‐831, 2007.
 2.Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J, Helin K. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A‐ARF locus in response to oncogene‐ and stress‐induced senescence. Genes Dev 23: 1171‐1176, 2009.
 3.Ahuja S, Kohli S, Krishnan S, Dogra D, Sharma D, Rani V. Curcumin: A potential therapeutic polyphenol, prevents noradrenaline‐induced hypertrophy in rat cardiac myocytes. J Pharm Pharmacol 63: 1604‐1612, 2011.
 4.Aisagbonhi O, Rai M, Ryzhov S, Atria N, Feoktistov I, Hatzopoulos AK. Experimental myocardial infarction triggers canonical Wnt signaling and endothelial‐to‐mesenchymal transition. Dis Model Mech 4: 469‐483, 2011.
 5.Akazawa H, Komuro I. Roles of cardiac transcription factors in cardiac hypertrophy. Circ Res 92: 1079‐1088, 2003.
 6.Akimova T, Beier UH, Liu YJ, Wang LQ, Hancock WW. Histone/protein deacetylases and T‐cell immune responses. Blood 119: 2443‐2451, 2012.
 7.Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, Tian B, Wagner T, Vatner SF, Sadoshima J. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res 100: 1512‐1521, 2007.
 8.Alvarez‐Errico D, Vento‐Tormo R, Sieweke M, Ballestar E. Epigenetic control of myeloid cell differentiation, identity and function. Nature Reviews Immunology 15: 7‐17, 2015.
 9.Angrisano T, Schiattarella GG, Keller S, Pironti G, Florio E, Magliulo F, Bottino R, Pero R, Lembo F, Avvedimento EV, Esposito G, Trimarco B, Chiariotti L, Perrino C. Epigenetic switch at Atp2a2 and Myh7 gene promoters in pressure overload‐induced heart failure. PLoS One 9: e106024, 2014.
 10.Antos CL, McKinsey TA, Dreitz M, Hollingsworth LM, Zhang CL, Schreiber K, Rindt H, Gorczynski RJ, Olson EN. Dose‐dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitors. J Biol Chem 278: 28930‐28937, 2003.
 11.Arndt S, Wacker E, Dorn C, Koch A, Saugspier M, Thasler WE, Hartmann A, Bosserhoff AK, Hellerbrand C. Enhanced expression of BMP6 inhibits hepatic fibrosis in non‐alcoholic fatty liver disease. Gut 64: 973‐981, 2015.
 12.Austenaa L, Barozzi I, Chronowska A, Termanini A, Ostuni R, Prosperini E, Stewart AF, Testa G, Natoli G. The histone methyltransferase Wbp7 controls macrophage function through GPI glycolipid anchor synthesis. Immunity 36: 572‐585, 2012.
 13.Avruch J, Xavier R, Bardeesy N, Zhang XF, Praskova M, Zhou D, Xia F. Rassf family of tumor suppressor polypeptides. J Biol Chem 284: 11001‐11005, 2009.
 14.Azevedo PS, Polegato BF, Minicucci MF, Paiva SAR, Zornoff LAM. Cardiac remodeling: Concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment. Arq Bras Cardiol 106: 62‐69, 2016.
 15.Babu M, Devi TD, Makinen P, Kaikkonen M, Lesch HP, Junttila S, Laiho A, Ghimire B, Gyenesei A, Yla‐Herttuala S. Differential promoter methylation of macrophage genes is associated with impaired vascular growth in ischemic muscles of hyperlipidemic and type 2 diabetic mice genome‐wide promoter methylation study. Circ Res 117: 289‐299, 2015.
 16.Baccarelli A, Wright R, Bollati V, Litonjua A, Zanobetti A, Tarantini L, Sparrow D, Vokonas P, Schwartz J. Ischemic heart disease and stroke in relation to blood DNA methylation. Epidemiology 21: 819‐828, 2010.
 17.Baik J, Rosania GR. Macrophages sequester clofazimine in an intracellular liquid crystal‐like supramolecular organization. PLoS One 7: e47494, 2012.
 18.Balakumar P, Singh M. Anti‐tumour necrosis factor‐alpha therapy in heart failure: Future directions. Basic Clin Pharmacol 99: 391‐397, 2006.
 19.Ball MP, Li JB, Gao Y, Lee JH, LeProust EM, Park IH, Xie B, Daley GQ, Church GM. Targeted and genome‐scale strategies reveal gene‐body methylation signatures in human cells. Nat Biotechnol 27: 361‐368, 2009.
 20.Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K. Immunobiology of dendritic cells. Annu Rev Immunol 18: 767‐811, 2000.
 21.Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 392: 245‐252, 1998.
 22.Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res 21: 381‐395, 2011.
 23.Bansal SS, Ismahil MA, Goel M, Patel B, Hamid T, Rokosh G, Prabhu SD. Activated T lymphocytes are essential drivers of pathological remodeling in ischemic heart failure. Circ‐Heart Fail 10: e003688, 2017.
 24.Barisione C, Garibaldi S, Ghigliotti G, Fabbi P, Altieri P, Casale MC, Spallarossa P, Bertero G, Balbi M, Corsiglia L, Brunelli C. CD14CD16 monocyte subset levels in heart failure patients. Dis Markers 28: 115‐124, 2010.
 25.Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: Importance in inflammatory lung diseases. Eur Respir J 25: 552‐563, 2005.
 26.Barrero MJ, Boue S, Belmonte JCI. Epigenetic mechanisms that regulate cell identity. Cell Stem Cell 7: 565‐570, 2010.
 27.Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kalbacher H, Salant DJ, Muller CA, Kalluri R, Zeisberg M. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 16: 544‐550, 2010.
 28.Beier UH, Akimova T, Liu Y, Wang L, Hancock WW. Histone/protein deacetylases control Foxp3 expression and the heat shock response of T‐regulatory cells. Curr Opin Immunol 23: 670‐678, 2011.
 29.Beier UH, Wang L, Han R, Akimova T, Liu Y, Hancock WW. Histone deacetylases 6 and 9 and sirtuin‐1 control Foxp3+ regulatory T cell function through shared and isoform‐specific mechanisms. Sci Signal 5: ra45, 2013.
 30.Bellenguez C, Bevan S, Gschwendtner A, Spencer CCA, Burgess AI, Pirinen M, Jackson CA, Traylor M, Strange A, Su Z, Band G, Syme PD, Malik R, Pera J, Norrving B, Lemmens R, Freeman C, Schanz R, James T, Poole D, Murphy L, Segal H, Cortellini L, Cheng YC, Woo D, Nalls MA, Muller‐Myhsok B, Meisinger C, Seedorf U, Ross‐Adams H, Boonen S, Wloch‐Kopec D, Valant V, Slark J, Furie K, Delavaran H, Langford C, Deloukas P, Edkins S, Hunt S, Gray E, Dronov S, Peltonen L, Gretarsdottir S, Thorleifsson G, Thorsteinsdottir U, Stefansson K, Boncoraglio GB, Parati EA, Attia J, Holliday E, Levi C, Franzosi MG, Goel A, Helgadottir A, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Duncanson A, Jankowski J, Mathew CG, Palmer CNA, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood NW, Worrall BB, Kittner SJ, Mitchell BD, Kissela B, Meschia JF, Thijs V, Lindgren A, Macleod MJ, Slowik A, Walters M, Rosand J, Sharma P, Farrall M, Sudlow CLM, Rothwell PM, Dichgans M, Donnelly P, Markus HS, Isgc, and Wtccc2. Genome‐wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nature Genetics 44: 328‐U141, 2012.
 31.Bergmann O, Zdunek S, Alkass K, Druid H, Bernard S, Frisen J. Identification of cardiomyocyte nuclei and assessment of ploidy for the analysis of cell turnover. Exp Cell Res 317: 188‐194, 2011.
 32.Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell 128: 669‐681, 2007.
 33.Bhattacharyya S, Ghosh AK, Pannu J, Mori Y, Takagawa S, Chen G, Trojanowska M, Gilliam AC, Varga J. Fibroblast expression of the coactivator p300 governs the intensity of profibrotic response to transforming growth factor beta. Arthritis Rheum 52: 1248‐1258, 2005.
 34.Black JC, Whetstine JR. Tipping the lysine methylation balance in disease. Biopolymers 99: 127‐135, 2013.
 35.Boheler KR, Volkova M, Morrell C, Garg R, Zhu Y, Margulies K, Seymour AM, Lakatta EG. Sex‐ and age‐dependent human transcriptome variability: Implications for chronic heart failure. Proc Natl Acad Sci U S A 100: 2754‐2759, 2003.
 36.Braunwald E. Biomarkers in heart failure. N Engl J Med 358: 2148‐2159, 2008.
 37.Braunwald E, Bristow MR. Congestive heart failure: Fifty years of progress. Circulation 102: IV14‐23, 2000.
 38.Brogdon JL, Xu Y, Szabo SJ, An S, Buxton F, Cohen D, Huang Q. Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood 109: 1123‐1130, 2007.
 39.Broske AM, Vockentanz L, Kharazi S, Huska MR, Mancini E, Scheller M, Kuhl C, Enns A, Prinz M, Jaenisch R, Nerlov C, Leutz A, Andrade‐Navarro MA, Jacobsen SE, Rosenbauer F. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet 41: 1207‐1215, 2009.
 40.Bujak M, Frangogiannis NG. The role of TGF‐beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74: 184‐195, 2007.
 41.Bullwinkel J, Ludemann A, Debarry J, Singh PB. Epigenotype switching at the CD14 and CD209 genes during differentiation of human monocytes to dendritic cells. Epigenetics‐Us 6: 45‐51, 2011.
 42.Burchfield JS, Xie M, Hill JA. Pathological ventricular remodeling: Mechanisms: Part 1 of 2. Circulation 128: 388‐400, 2013.
 43.Cai CL, Martin JC, Sun Y, Cui L, Wang L, Ouyang K, Yang L, Bu L, Liang X, Zhang X, Stallcup WB, Denton CP, McCulloch A, Chen J, Evans SM. A myocardial lineage derives from Tbx18 epicardial cells. Nature 454: 104‐108, 2008.
 44.Camelliti P, Borg TK, Kohl P. Structural and functional characterisation of cardiac fibroblasts. Cardiovasc Res 65: 40‐51, 2005.
 45.Cao Q, Rong SX, Repa JJ, St Clair R, Parks JS, Mishra N. Histone deacetylase 9 represses cholesterol efflux and alternatively activated macrophages in atherosclerosis development. Arterioscl Throm Vas 34: 1871‐1879, 2014.
 46.Cao Q, Wang XF, Jia L, Mondal AK, Diallo A, Hawkins GA, Das SK, Parks JS, Yu LQ, Shi HD, Shi H, Xue BZ. Inhibiting DNA methylation by 5‐Aza‐2′‐deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation. Endocrinology 155: 4925‐4938, 2014.
 47.Cardinale JP, Sriramula S, Pariaut R, Guggilam A, Mariappan N, Elks CM, Francis J. HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats. Hypertension 56: 437‐U196, 2010.
 48.Care A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, Bang ML, Segnalini P, Gu Y, Dalton ND, Elia L, Latronico MV, Hoydal M, Autore C, Russo MA, Dorn GW, II, Ellingsen O, Ruiz‐Lozano P, Peterson KL, Croce CM, Peschle C, Condorelli G. MicroRNA‐133 controls cardiac hypertrophy. Nat Med 13: 613‐618, 2007.
 49.Castillo‐Diaz SA, Garay‐Sevilla ME, Hernandez‐Gonzalez MA, Solis‐Martinez MO, Zaina S. Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries. Int J Mol Med 26: 691‐700, 2010.
 50.Cataldi M, Vigliotti C, Mosca T, Cammarota M, Capone D. Emerging role of the spleen in the pharmacokinetics of monoclonal antibodies, nanoparticles and exosomes. Int J Mol Sci 18: 2017.
 51.Chalitchagorn K, Shuangshoti S, Hourpai N, Kongruttanachok N, Tangkijvanich P, Thong‐ngam D, Voravud N, Sriuranpong V, Mutirangura A. Distinctive pattern of LINE‐1 methylation level in normal tissues and the association with carcinogenesis. Oncogene 23: 8841‐8846, 2004.
 52.Challen GA, Sun D, Mayle A, Jeong M, Luo M, Rodriguez B, Mallaney C, Celik H, Yang L, Xia Z, Cullen S, Berg J, Zheng Y, Darlington GJ, Li W, Goodell MA. Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells. Cell Stem Cell 15: 350‐364, 2014.
 53.Chang S, McKinsey TA, Zhang CL, Richardson JA, Hill JA, Olson EN. Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol Cell Biol 24: 8467‐8476, 2004.
 54.Chapman CG, Mariani CJ, Wu F, Meckel K, Butun F, Chuang A, Madzo J, Bissonnette MB, Kwon JH, Godley LA. TET‐catalyzed 5‐hydroxymethylcytosine regulates gene expression in differentiating colonocytes and colon cancer. Sci Rep 5: 17568, 2015.
 55.Chaturvedi P, Kalani A, Givvimani S, Kamat PK, Familtseva A, Tyagi SC. Differential regulation of DNA methylation versus histone acetylation in cardiomyocytes during HHcy in vitro and in vivo: An epigenetic mechanism. Physiol Genomics 46: 245‐255, 2014.
 56.Chauvistre H, Kustermann C, Rehage N, Klisch T, Mitzka S, Felker P, Rose‐John S, Zenke M, Sere KM. Dendritic cell development requires histone deacetylase activity. Eur J Immunol 44: 2478‐2488, 2014.
 57.Chavali V, Tyagi SC, Mishra PK. MicroRNA‐133a regulates DNA methylation in diabetic cardiomyocytes. Biochem Bioph Res Co 425: 668‐672, 2012.
 58.Chen XF, Barozzi I, Termanini A, Prosperini E, Recchiuti A, Dalli J, Mietton F, Matteoli G, Hiebert S, Natoli G. Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. P Natl Acad Sci USA 109: E2865‐E2874, 2012.
 59.Chen Z, Miao F, Paterson AD, Lachin JM, Zhang L, Schones DE, Wu X, Wang J, Tompkins JD, Genuth S, Braffett BH, Riggs AD, Natarajan R. Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort. Proc Natl Acad Sci U S A 113: E3002‐3011, 2016.
 60.Cheng C, Huang C, Ma TT, Bian EB, He Y, Zhang L, Li J. SOCS1 hypermethylation mediated by DNMT1 is associated with lipopolysaccharide‐induced inflammatory cytokines in macrophages. Toxicol Lett 225: 488‐497, 2014.
 61.Cheng C, Wang SH, Ye P, Huang XF, Liu Z, Wu J, Sun Y, Xie AN, Wang GH, Xia JH. ‘Default’ generated neonatal regulatory T cells are hypomethylated at conserved non‐coding sequence 2 and promote long‐term cardiac allograft survival. Immunology 143: 618‐630, 2014.
 62.Cheong C, Matos I, Choi JH, Dandamudi DB, Shrestha E, Longhi MP, Jeffrey KL, Anthony RM, Kluger C, Nchinda G, Koh H, Rodriguez A, Idoyaga J, Pack M, Velinzon K, Park CG, Steinman RM. Microbial stimulation fully differentiates monocytes to DC‐SIGN/CD209(+) dendritic cells for immune T cell areas. Cell 143: 416‐429, 2010.
 63.Chien KR, Knowlton KU, Zhu H, Chien S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: Molecular studies of an adaptive physiologic response. FASEB J 5: 3037‐3046, 1991.
 64.Chung YL, Lee MY, Wang AJ, Yao LF. A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis. Mol Ther 8: 707‐717, 2003.
 65.Ciavatta DJ, Yang J, Preston GA, Badhwar AK, Xiao H, Hewins P, Nester CM, Pendergraft WF, III, Magnuson TR, Jennette JC, Falk RJ. Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J Clin Invest 120: 3209‐3219, 2010.
 66.Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling–‐concepts and clinical implications: A consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol 35: 569‐582, 2000.
 67.Coletta AP, Clark AL, Banarjee P, Cleland JG. Clinical trials update: RENEWAL (RENAISSANCE and RECOVER) and ATTACH. Eur J Heart Fail 4: 559‐561, 2002.
 68.Collier P, Watson CJ, van Es MH, Phelan D, McGorrian C, Tolan M, Ledwidge MT, McDonald KM, Baugh JA. Getting to the heart of cardiac remodeling; how collagen subtypes may contribute to phenotype. J Mol Cell Cardiol 52: 148‐153, 2012.
 69.Coward WR, Feghali‐Bostwick CA, Jenkins G, Knox AJ, Pang LH. A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase‐2 in idiopathic pulmonary fibrosis. FASEB J 28: 3183‐3196, 2014.
 70.Cui K, Zang C, Roh TY, Schones DE, Childs RW, Peng W, Zhao K. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell 4: 80‐93, 2009.
 71.Das Gupta K, Shakespear MR, Iyer A, Fairlie DP, Sweet MJ. Histone deacetylases in monocyte/macrophage development, activation and metabolism: Refining HDAC targets for inflammatory and infectious diseases. Clin Transl Immunology 5: e62, 2016.
 72.Das PM, Singal R. DNA methylation and cancer. J Clin Oncol 22: 4632‐4642, 2004.
 73.de Haan JJ, Smeets MB, Pasterkamp G, Arslan F. Danger signals in the initiation of the inflammatory response after myocardial infarction. Mediators Inflamm 2013: 206039, 2013.
 74.de Mello VDF, Pulkkinen L, Lalli M, Kolehmainen M, Pihlajamäki J, Uusitupa M. DNA methylation in obesity and type 2 diabetes. Ann Med 46: 103‐113, 2014.
 75.de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem J 370: 737‐749, 2003.
 76.de Zoeten EF, Wang L, Butler K, Beier UH, Akimova T, Sai H, Bradner JE, Mazitschek R, Kozikowski AP, Matthias P, Hancock WW. Histone Deacetylase 6 and heat shock protein 90 control the functions of Foxp3+ T‐regulatory cells. Mol Cell Biol 31: 2066‐2078, 2011.
 77.de Zoeten EF, Wang L, Sai H, Dillmann WH, Hancock WW. Inhibition of HDAC9 increases T regulatory cell function and prevents colitis in mice. Gastroenterology 138: 583‐594, 2010.
 78.Deaton AM, Bird A. CpG islands and the regulation of transcription. Gene Dev 25: 1010‐1022, 2011.
 79.Del Re DP, Matsuda T, Zhai P, Gao S, Clark GJ, Van Der Weyden L, Sadoshima J. Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice. J Clin Invest 120: 3555‐3567, 2010.
 80.Demos‐Davies KM, Ferguson BS, Cavasin MA, Mahaffey JH, Williams SM, Spiltoir JI, Schuetze KB, Horn TR, Chen B, Ferrara C, Scellini B, Piroddi N, Tesi C, Poggesi C, Jeong MY, McKinsey TA. HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin‐II signaling. Am J Physiol Heart Circ Physiol 307: H252‐258, 2014.
 81.Desmouliere A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 146: 56‐66, 1995.
 82.Doetschman T, Azhar M. Cardiac‐specific inducible and conditional gene targeting in mice. Circ Res 110: 1498‐1512, 2012.
 83.Du J, Zhang L, Zhuang S, Qin GJ, Zhao TC. HDAC4 degradation mediates HDAC inhibition‐induced protective effects against hypoxia/reoxygenation injury. J Cell Physiol 230: 1321‐1331, 2015.
 84.Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429: 457‐463, 2004.
 85.Epelman S, Lavine KJ, Beaudin AE, Sojka DK, Carrero JA, Calderon B, Brija T, Gautier EL, Ivanov S, Satpathy AT, Schilling JD, Schwendener R, Sergin I, Razani B, Forsberg EC, Yokoyama WM, Unanue ER, Colonna M, Randolph GJ, Mann DL. Embryonic and adult‐derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40: 91‐104, 2014.
 86.Epelman S, Liu PP, Mann DL. Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat Rev Immunol 15: 117‐129, 2015.
 87.Escobar TM, Kanellopoulou C, Kugler DG, Kilaru G, Nguyen CK, Nagarajan V, Bhairavabhotla RK, Northrup D, Zahr R, Burr P, Liu X, Zhao K, Sher A, Jankovic D, Zhu J, Muljo SA. miR‐155 activates cytokine gene expression in Th17 cells by regulating the DNA‐binding protein Jarid2 to relieve polycomb‐mediated repression. Immunity 40: 865‐879, 2014.
 88.Fan D, Takawale A, Lee J, Kassiri Z. Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair 5: 15, 2012.
 89.Fang TC, Schaefer U, Mecklenbrauker I, Stienen A, Dewell S, Chen MS, Rioja I, Parravicini V, Prinjha RK, Chandwani R, MacDonald MR, Lee K, Rice CM, Tarakhovsky A. Histone H3 lysine 9 di‐methylation as an epigenetic signature of the interferon response. J Exp Med 209: 661‐669, 2012.
 90.Fang XF, Poulsen RR, Wang‐Hu J, Shi O, Calvo NS, Simmons CS, Rivkees SA, Wendler CC. Knockdown of DNA methyltransferase 3a alters gene expression and inhibits function of embryonic cardiomyocytes. FASEB J 30: 3238‐3255, 2016.
 91.Faraco G, Cavone L, Chiarugi A. The therapeutic potential of HDAC inhibitors in the treatment of multiple sclerosis. Mol Med 17: 442‐447, 2011.
 92.Feng D, Sangster‐Guity N, Stone R, Korczeniewska J, Mancl ME, Fitzgerald‐Bocarsly P, Barnes BJ. Differential requirement of histone acetylase and deacetylase activities for IRF5‐mediated proinflammatory cytokine expression. J Immunol 185: 6003‐6012, 2010.
 93.Flanagan JM, Wild L. An epigenetic role for noncoding RNAs and intragenic DNA methylation. Genome Biol 8: 307, 2007.
 94.Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E, Klein‐Hessling S, Serfling E, Hamann A, Huehn J. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5: e38, 2007.
 95.Forster O, Hilfiker‐Kleiner D, Ansari AA, Sundstrom JB, Libhaber E, Tshani W, Becker A, Yip A, Klein G, Sliwa K. Reversal of IFN‐gamma, oxLDL and prolactin serum levels correlate with clinical improvement in patients with peripartum cardiomyopathy. Eur J Heart Fail 10: 861‐868, 2008.
 96.Foster SL, Hargreaves DC, Medzhitov R. Gene‐specific control of inflammation by TLR‐induced chromatin modifications. Nature 447: 972‐978, 2007.
 97.Fraineau S, Palii CG, Allan DS, Brand M. Epigenetic regulation of endothelial‐cell‐mediated vascular repair. FEBS J 282: 1605‐1629, 2015.
 98.Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Circ Res 110: 159‐173, 2012.
 99.Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol 11: 255‐265, 2014.
 100.Frangogiannis NG. The extracellular matrix in myocardial injury, repair, and remodeling. J Clin Invest 127: 1600‐1612, 2017.
 101.Friedman SL. Fibrogenic cell reversion underlies fibrosis regression in liver. P Natl Acad Sci USA 109: 9230‐9231, 2012.
 102.Frikeche J, Clavert A, Delaunay J, Brissot E, Gregoire M, Gaugler B, Mohty M. Impact of the hypomethylating agent 5‐azacytidine on dendritic cells function. Exp Hematol 39: 1056‐1063, 2011.
 103.Frikeche J, Peric Z, Brissot E, Gregoire M, Gaugler B, Mohty M. Impact of HDAC inhibitors on dendritic cell functions. Exp Hematol 40: 783‐791, 2012.
 104.Fukunaga T, Soejima H, Irie A, Sugamura K, Oe Y, Tanaka T, Nagayoshi Y, Kaikita K, Sugiyama S, Yoshimura M, Nishimura Y, Ogawa H. Relation between CD4+ T‐cell activation and severity of chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 100: 483‐488, 2007.
 105.Gallagher KA, Joshi A, Carson WF, Schaller M, Allen R, Mukerjee S, Kittan N, Feldman EL, Henke PK, Hogaboam C, Burant CF, Kunkel SL. Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes. Diabetes 64: 1420‐1430, 2015.
 106.Gallo P, Latronico MV, Grimaldi S, Borgia F, Todaro M, Jones P, Gallinari P, De Francesco R, Ciliberto G, Steinkuhler C, Esposito G, Condorelli G. Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure. Cardiovasc Res 80: 416‐424, 2008.
 107.Gerber Y, Weston SA, Redfield MM, Chamberlain AM, Manemann SM, Jiang RX, Killian JM, Roger VL. A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010. Jama Intern Med 175: 996‐1004, 2015.
 108.Ghisletti S, Barozzi I, Mietton F, Polletti S, De Santa F, Venturini E, Gregory L, Lonie L, Chew A, Wei CL, Ragoussis J, Natoli G. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32: 317‐328, 2010.
 109.Gilsbach R, Preissl S, Gruning BA, Schnick T, Burger L, Benes V, Wurch A, Bonisch U, Gunther S, Backofen R, Fleischmann BK, Schubeler D, Hein L. Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease. Nat Commun 5: 5288, 2014.
 110.Glenisson W, Castronovo V, Waltregny D. Histone deacetylase 4 is required for TGFbeta1‐induced myofibroblastic differentiation. Biochim Biophys Acta 10: 12, 2007.
 111.Glezeva N, Horgan S, Baugh JA. Monocyte and macrophage subsets along the continuum to heart failure: Misguided heroes or targetable villains? J Mol Cell Cardiol 89: 136‐145, 2015.
 112.Glezeva N, Voon V, Watson C, Horgan S, McDonald K, Ledwidge M, Baugh J. Exaggerated inflammation and monocytosis associate with diastolic dysfunction in heart failure with preserved ejection fraction: Evidence of M2 macrophage activation in disease pathogenesis. J Card Fail 21: 167‐177, 2015.
 113.Goffin J, Eisenhauer E. DNA methyltransferase inhibitors‐state of the art. Ann Oncol 13: 1699‐1716, 2002.
 114.Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 5: 953‐964, 2005.
 115.Greco CM, Condorelli G. Epigenetic modifications and noncoding RNAs in cardiac hypertrophy and failure. Nat Rev Cardiol 12: 488‐497, 2015.
 116.Greco CM, Kunderfranco P, Rubino M, Larcher V, Carullo P, Anselmo A, Kurz K, Carell T, Angius A, Latronico MVG, Papait R, Condorelli G. DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy. Nat Commun 7: 12418, 2016.
 117.Grzeskowiak R, Witt H, Drungowski M, Thermann R, Hennig S, Perrot A, Osterziel KJ, Klingbiel D, Scheid S, Spang R, Lehrach H, Ruiz P. Expression profiling of human idiopathic dilated cardiomyopathy. Cardiovasc Res 59: 400‐411, 2003.
 118.Gullestad L, Ueland T, Vinge LE, Finsen A, Yndestad A, Aukrust P. Inflammatory cytokines in heart failure: Mediators and markers. Cardiology 122: 23‐35, 2012.
 119.Guo W, Shan B, Klingsberg RC, Qin X, Lasky JA. Abrogation of TGF‐beta1‐induced fibroblast‐myofibroblast differentiation by histone deacetylase inhibition. Am J Physiol Lung Cell Mol Physiol 297: L864‐870, 2009.
 120.Gusterson RJ, Jazrawi E, Adcock IM, Latchman DS. 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. J Biol Chem 278: 6838‐6847, 2003.
 121.Haas J, Frese KS, Park YJ, Keller A, Vogel B, Lindroth AM, Weichenhan D, Franke J, Fischer S, Bauer A, Marquart S, Sedaghat‐Hamedani F, Kayvanpour E, Kohler D, Wolf NM, Hassel S, Nietsch R, Wieland T, Ehlermann P, Schultz JH, Dosch A, Mereles D, Hardt S, Backs J, Hoheisel JD, Plass C, Katus HA, Meder B. Alterations in cardiac DNA methylation in human dilated cardiomyopathy. Embo Mol Med 5: 413‐429, 2013.
 122.Haery L, Thompson RC, Gilmore TD. Histone acetyltransferases and histone deacetylases in B‐ and T‐cell development, physiology and malignancy. Genes Cancer 6: 184, 2015.
 123.Hafner AV, Dai J, Gomes AP, Xiao CY, Palmeira CM, Rosenzweig A, Sinclair DA. Regulation of the mPTP by SIRT3‐mediated deacetylation of CypD at lysine 166 suppresses age‐related cardiac hypertrophy. Aging 2: 914‐923, 2010.
 124.Han P, Li W, Lin CH, Yang J, Shang C, Nuernberg ST, Jin KK, Xu W, Lin CY, Lin CJ, Xiong Y, Chien H, Zhou B, Ashley E, Bernstein D, Chen PS, Chen HV, Quertermous T, Chang CP. A long noncoding RNA protects the heart from pathological hypertrophy. Nature 514: 102‐106, 2014.
 125.Han ZH, Dong X, Zhang CY, Wu Y, Yuan ZY, Wang XH. Polymorphism of HDAC9 gene is associated with increased risk of acute coronary syndrome in Chinese Han population. Biomed Res Int 2016: 3746276, 2016.
 126.He HQ, Ni B, Tian Y, Tian ZQ, Chen YK, Liu ZW, Yang XM, Lv Y, Zhang Y. Histone methylation mediates plasticity of human FOXP3+ regulatory T cells by modulating signature gene expressions. Immunology 141: 362‐376, 2014.
 127.He S, Tong Q, Bishop DK, Zhang Y. Histone methyltransferase and histone methylation in inflammatory T‐cell responses. Immunotherapy‐Uk 5: 989‐1004, 2013.
 128.Heidecker B, Kasper EK, Wittstein IS, Champion HC, Breton E, Russell SD, Kittleson MM, Baughman KL, Hare JM. Transcriptomic biomarkers for individual risk assessment in new‐onset heart failure. Circulation 118: 238‐246, 2008.
 129.Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC, Ikonomidis JS, Khavjou O, Konstam MA, Maddox TM, Nichol G, Pham M, Pina IL, Trogdon JG, American Heart Association Advocacy Coordinating C, Council on Arteriosclerosis T, Vascular B, Council on Cardiovascular R, Intervention, Council on Clinical C, Council on E, Prevention, and Stroke C. Forecasting the impact of heart failure in the United States: A policy statement from the American Heart Association. Circ Heart Fail 6: 606‐619, 2013.
 130.Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK. Simple combinations of lineage‐determining transcription factors prime cis‐regulatory elements required for macrophage and B cell identities. Mol Cell 38: 576‐589, 2010.
 131.Hellman A, Chess A. Gene body‐specific methylation on the active X chromosome. Science 315: 1141‐1143, 2007.
 132.Hendrich B, Tweedie S. The methyl‐CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet 19: 269‐277, 2003.
 133.Hiltunen MO, Turunen MP, Hakkinen TP, Rutanen J, Hedman M, Makinen K, Turunen AM, Aalto‐Setala K, Yla‐Herttuala S. DNA hypomethylation and methyltransferase expression in atherosclerotic lesions. Vasc Med 7: 5‐11, 2002.
 134.Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton‐Piallat ML, Gabbiani G. The myofibroblast: One function, multiple origins. Am J Pathol 170: 1807‐1816, 2007.
 135.Hirahara K, Vahedi G, Ghoreschi K, Yang XP, Nakayamada S, Kanno Y, O'Shea JJ, Laurence A. Helper T‐cell differentiation and plasticity: Insights from epigenetics. Immunology 134: 235‐245, 2011.
 136.Hoeksema MA, Gijbels MJJ, Van den Bossche J, van der Velden S, Sijm A, Neele AE, Seijkens T, Stoger JL, Meiler S, Boshuizen MCS, Dallinga‐Thie GM, Levels JHM, Boon L, Mullican SE, Spann NJ, Cleutjens JP, Glass CK, Lazar MA, de Vries CJM, Biessen EAL, Daemen MJAP, Lutgens E, de Winther MPJ. Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions. Embo Mol Med 6: 1124‐1132, 2014.
 137.Hohl M, Wagner M, Reil JC, Muller SA, Tauchnitz M, Zimmer AM, Lehmann LH, Thiel G, Bohm M, Backs J, Maack C. HDAC4 controls histone methylation in response to elevated cardiac load. J Clin Invest 123: 1359‐1370, 2013.
 138.Holoch D, Moazed D. RNA‐mediated epigenetic regulation of gene expression. Nat Rev Genet 16: 71‐84, 2015.
 139.Homeister JW, Lucchesi BR. Complement activation and inhibition in myocardial ischemia and reperfusion injury. Annu Rev Pharmacol Toxicol 34: 17‐40, 1994.
 140.Hosenpud JD, Greenberg BH. Congestive Heart Failure, USA: Lippincott Williams & Wilkins, 2007.
 141.Huan C, Yang T, Liang J, Xie T, Cheng L, Liu N, Kurkciyan A, Monterrosa Mena J, Wang C, Dai H, Noble PW, Jiang D. Methylation‐mediated BMPER expression in fibroblast activation in vitro and lung fibrosis in mice in vivo. Sci Rep 5: 14910, 2015.
 142.Huang LX, Xi ZH, Wang CG, Zhang YY, Yang ZB, Zhang SQ, Chen YX, Zuo ZH. Phenanthrene exposure induces cardiac hypertrophy via reducing miR‐133a expression by DNA methylation. Sci Rep 6: 20105, 2016.
 143.Huehn J, Polansky JK, Hamann A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T‐cell lineage? Nat Rev Immunol 9: 83‐89, 2009.
 144.Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD‐dependent histone deacetylase. Nature 403: 795‐800, 2000.
 145.Irifuku T, Doi S, Sasaki K, Doi T, Nakashima A, Ueno T, Yamada K, Arihiro K, Kohno N, Masaki T. Inhibition of H3K9 histone methyltransferase G9a attenuates renal fibrosis and retains klotho expression. Kidney Int 89: 147‐157, 2016.
 146.Ishii M, Wen H, Corsa CA, Liu T, Coelho AL, Allen RM, Carson WFt, Cavassani KA, Li X, Lukacs NW, Hogaboam CM, Dou Y, Kunkel SL. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood 114: 3244‐3254, 2009.
 147.Ismahil MA, Hamid T, Bansal SS, Patel B, Kingery JR, Prabhu SD. Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: Critical importance of the cardiosplenic axis. Circ Res 114: 266‐282, 2014.
 148.Iyer A, Fenning A, Lim J, Le GT, Reid RC, Halili MA, Fairlie DP, Brown L. Antifibrotic activity of an inhibitor of histone deacetylases in DOCA‐salt hypertensive rats. Br J Pharmacol 159: 1408‐1417, 2010.
 149.Jaenisch R, Bird A. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet 33(Suppl): 245‐254, 2003.
 150.Jankowska AM, Makishima H, Tiu RV, Szpurka H, Huang Y, Traina F, Visconte V, Sugimoto Y, Prince C, O'Keefe C, Hsi ED, List A, Sekeres MA, Rao A, McDevitt MA, Maciejewski JP. Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood 118: 3932‐3941, 2011.
 151.Janzer A, Stamm K, Becker A, Zimmer A, Buettner R, Kirfel J. The H3K4me3 histone demethylase Fbxl10 is a regulator of chemokine expression, cellular morphology, and the metabolome of fibroblasts. J Biol Chem 287: 30984‐30992, 2012.
 152.Jeong HY, Kang WS, Hong MH, Jeong HC, Shin MG, Jeong MH, Kim YS, Ahn Y. 5‐Azacytidine modulates interferon regulatory factor 1 in macrophages to exert a cardioprotective effect. Sci Rep 5: 15768, 2015.
 153.Ji H, Ehrlich LI, Seita J, Murakami P, Doi A, Lindau P, Lee H, Aryee MJ, Irizarry RA, Kim K, Rossi DJ, Inlay MA, Serwold T, Karsunky H, Ho L, Daley GQ, Weissman IL, Feinberg AP. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467: 338‐342, 2010.
 154.Ji H, Ehrlich LIR, Seita J, Murakami P, Doi A, Lindau P, Lee H, Aryee MJ, Irizarry RA, Kim K, Rossi DJ, Inlay MA, Serwold T, Karsunky H, Ho LN, Daley GQ, Weissman IL, Feinberg AP. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467: 338‐U120, 2010.
 155.Jones B, Chen J. Inhibition of IFN‐gamma transcription by site‐specific methylation during T helper cell development. Embo J 25: 2443‐2452, 2006.
 156.Jordana M, Schulman J, McSharry C, Irving LB, Newhouse MT, Jordana G, Gauldie J. Heterogeneous proliferative characteristics of human adult lung fibroblast lines and clonally derived fibroblasts from control and fibrotic tissue. Am Rev Respir Dis 137: 579‐584, 1988.
 157.Jugdutt BI. Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways. Curr Drug Targets Cardiovasc Haematol Disord 3: 1‐30, 2003.
 158.Jugdutt BI. Ventricular remodeling after infarction and the extracellular collagen matrix: When is enough enough? Circulation 108: 1395‐1403, 2003.
 159.Kaneda R, Takada S, Yamashita Y, Choi YL, Nonaka‐Sarukawa M, Soda M, Misawa Y, Isomura T, Shimada K, Mano H. Genome‐wide histone methylation profile for heart failure. Genes Cells 14: 69‐77, 2009.
 160.Kao YH, Liou JP, Chung CC, Lien GS, Kuo CC, Chen SA, Chen YJ. Histone deacetylase inhibition improved cardiac functions with direct antifibrotic activity in heart failure. Int J Cardiol 168: 4178‐4183, 2013.
 161.Kapellos TS, Iqbal AJ. Epigenetic control of macrophage polarisation and soluble mediator gene expression during inflammation. Mediat Inflamm 2016: 6591703, 2016.
 162.Kato N, Loh M, Takeuchi F, Verweij N, Wang X, Zhang WH, Kelly TN, Saleheen D, Lehne B, Leach IM, Drong AW, Abbott J, Wahl S, Tan ST, Scott WR, Campanella G, Chadeau‐Hyam M, Afzal U, Ahluwalia TS, Bonder MJ, Chen P, Dehghan A, Edwards TL, Esko T, Go MJ, Harris SE, Hartiala J, Kasela S, Kasturiratne A, Khor CC, Kleber ME, Li HX, Mok ZY, Nakatochi M, Sapari NS, Saxena R, Stewart AFR, Stolk L, Tabara Y, Teh AL, Wu Y, Wu JY, Zhang Y, Aits I, Alves ADC, Das S, Dorajoo R, Hopewell JC, Kim YK, Koivula RW, Luan J, Lyytikainen LP, Nguyen QN, Pereira MA, Postmus I, Raitakari OT, Bryan MS, Scott RA, Sorice R, Tragante V, Traglia M, White J, Yamamoto K, Zhang YH, Adair LS, Ahmed A, Akiyama K, Asif R, Aung T, Barroso I, Bjonnes A, Braun TR, Cai H, Chang LC, Chen CH, Cheng CY, Chong YS, Collins R, Courtney R, Davies G, Delgado G, Do LD, Doevendans PA, Gansevoort RT, Gao YT, Grammer TB, Grarup N, Grewal J, Gu DF, Wander GS, Hartikainen AL, Hazen SL, He J, Heng CK, Hixson JE, Hofman A, Hsu C, Huang W, Husemoen LLN, Hwang JY, Ichihara S, Igase M, Isono M, Justesen JM, Katsuy T, Kibriya MG, Kim YJ, Kishimoto M, Koh WP, Kohara K, Kumari M, Kwek K, Lee NR, Lee J, Liao JM, Lieb W, Liewald DCM, Matsubara T, Matsushita Y, Meitinger T, Mihailov E, Milani L, Mills R, Mononen N, Muller‐Nurasyid M, Nabika T, Nakashima E, Ng HK, Nikus K, Nutile T, Ohkubo T, Ohnaka K, Parish S, Paternoster L, Peng H, Peters A, Pham ST, Pinidiyapathirage MJ, Rahman M, Rakugi H, Rolandsson O, Rozario MA, Ruggiero D, Sala CF, Sarju R, Shimokawa K, Snieder H, Sparso T, Spiering W, Starr JM, Stott DJ, Stram DO, Sugiyama T, Szymczak S, Tang WHW, Tong L, Trompet S, Turjanmaa V, Ueshima H, Uitterlinden AG, Umemura S, Vaarasmaki M, van Dam RM, van Gilst WH, van Veldhuisen DJ, Viikari JS, Waldenberger M, Wang YQ, Wang AL, Wilson R, Wong TY, Xiang YB, Yamaguchi S, Ye XW, Young RD, Young TL, Yuan JM, Zhou XY, Asselbergs FW, Ciullo M, Clarke R, Deloukas P, Franke A, Franks PW, Franks S, Friedlander Y, Gross MD, Guo ZR, Hansen T, Jarvelin MR, Jorgensen T, Jukema JW, Kahonen M, Kajio H, Kivimaki M, Lee JY, Lehtimaki T, Linneberg A, Miki T, Pedersen O, Samani NJ, Sorensen TIA, Takayanagi R, Toniolo D, Ahsan H, Allayee H, Chen YT, Danesh J, Deary IJ, Franco OH, Franke L, Heijman BT, Holbrook JD, Isaacs A, Kim BJ, Lin X, Liu JJ, Marz W, Metspalu A, Mohlke KL, Sanghera DK, Shu XO, van Meurs JBJ, Vithana E, Wickremasinghe AR, Wijmenga C, Wolffenbuttel BHW, Yokota M, Zheng W, Zhu DL, Vineis P, Kyrtopoulos SA, Kleinjans JCS, McCarthy MI, Soong R, Gieger C, Scott J, Teo YY, He J, Elliott P, Tai ES, van der Harst P, Kooner JS, Chambers JC, BIOS‐consortium, GRAMplusCD C, Study LC, and Consortium I. Trans‐ancestry genome‐wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Nature Genet 47: 1282‐1293, 2015.
 163.Kee HJ, Kook H. Kruppel‐like factor 4 mediates histone deacetylase inhibitor‐induced prevention of cardiac hypertrophy. J Mol Cell Cardiol 47: 770‐780, 2009.
 164.Kee HJ, Sohn IS, Nam KI, Park JE, Qian YR, Yin Z, Ahn Y, Jeong MH, Bang YJ, Kim N, Kim JK, Kim KK, Epstein JA, Kook H. Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation 113: 51‐59, 2006.
 165.Kehat I, Molkentin JD. Molecular pathways underlying cardiac remodeling during pathophysiological stimulation. Circulation 122: 2727‐2735, 2010.
 166.Kemp CD, Conte JV. The pathophysiology of heart failure. Cardiovasc Pathol 21: 365‐371, 2012.
 167.Kim HP, Leonard WJ. CREB/ATF‐dependent T cell receptor‐induced FoxP3 gene expression: A role for DNA methylation. J Exp Med 204: 1543‐1551, 2007.
 168.Kim YS, Kang WS, Kwon JS, Hong MH, Jeong H‐y, Jeong HC, Jeong MH, Ahn Y. Protective role of 5‐azacytidine on myocardial infarction is associated with modulation of macrophage phenotype and inhibition of fibrosis. J Cell Mol Med 18: 1018‐1027, 2014.
 169.Kittan NA, Allen RM, Dhaliwal A, Cavassani KA, Schaller M, Gallagher KA, Carson WF, Mukherjee S, Grembecka J, Cierpicki T, Jarai G, Westwick J, Kunkel SL, Hogaboam CM. Cytokine induced phenotypic and epigenetic signatures are key to establishing specific macrophage phenotypes. PLoS One 8: e78045, 2013.
 170.Klug M, Schmidhofer S, Gebhard C, Andreesen R, Rehli M. 5‐Hydroxymethylcytosine is an essential intermediate of active DNA demethylation processes in primary human monocytes. Genome Biol 14: R46, 2013.
 171.Knosp CA, Schiering C, Spence S, Carroll HP, Nel HJ, Osbourn M, Jackson R, Lyubomska O, Malissen B, Ingram R, Fitzgerald DC, Powrie F, Fallon PG, Johnston JA, Kissenpfennig A. Regulation of Foxp3(+) inducible regulatory T cell stability by SOCS2. J Immunol 190: 3235‐3245, 2013.
 172.Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, Tsangaratou A, Rajewsky K, Koralov SB, Rao A. Ten‐Eleven‐Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. P Natl Acad Sci USA 108: 14566‐14571, 2011.
 173.Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502: 472‐479, 2013.
 174.Kolwicz SC, Purohit S, Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ Res 113: 603‐616, 2013.
 175.Komori HK, Hart T, LaMere SA, Chew PV, Salomon DR. Defining CD4 T cell memory by the epigenetic landscape of CpG DNA methylation. J Immunol 194: 1565‐1579, 2015.
 176.Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci 71: 549‐574, 2014.
 177.Kong Y, Tannous P, Lu G, Berenji K, Rothermel BA, Olson EN, Hill JA. Suppression of class I and II histone deacetylases blunts pressure‐overload cardiac hypertrophy. Circulation 113: 2579‐2588, 2006.
 178.Kooistra SM, Helin K. Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Bio 13: 297‐311, 2012.
 179.Kouzarides T. Chromatin modifications and their function. Cell 128: 693‐705, 2007.
 180.Kuroda A, Rauch TA, Todorov I, Ku HT, Al‐Abdullah IH, Kandeel F, Mullen Y, Pfeifer GP, Ferreri K. Insulin gene expression is regulated by DNA methylation. PLoS One 4: e6953, 2009.
 181.Kvakan H, Kleinewietfeld M, Qadri F, Park JK, Fischer R, Schwarz I, Rahn HP, Plehm R, Wellner M, Elitok S, Gratze P, Dechend R, Luft FC, Muller DN. Regulatory T cells ameliorate angiotensin II‐induced cardiac damage. Circulation 119: 2904‐2912, 2009.
 182.Lai MJ, Huang HL, Pan SL, Liu YM, Peng CY, Lee HY, Yeh TK, Huang PH, Teng CM, Chen CS, Chuang HY, Liou JP. Synthesis and biological evaluation of 1‐Arylsulfonyl‐5‐(N‐hydroxyacrylamide)indoles as potent histone deacetylase inhibitors with antitumor activity in vivo. J Med Chem 55: 3777‐3791, 2012.
 183.Lam CSP, Donal E, Kraigher‐Krainer E, Vasan RS. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail 13: 18‐28, 2011.
 184.Laroumanie F, Douin‐Echinard V, Pozzo J, Lairez O, Tortosa F, Vinel C, Delage C, Calise D, Dutaur M, Parini A, Pizzinat N. CD4(+) T cells promote the transition from hypertrophy to heart failure during chronic pressure overload. Circulation 129: 2111‐2124, 2014.
 185.Laviades C, Varo N, Fernandez J, Mayor G, Gil MJ, Monreal I, Diez J. Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation 98: 535‐540, 1998.
 186.Lee HY, Choi K, Oh H, Park YK, Park H. HIF‐1‐dependent induction of Jumonji domain‐containing protein (JMJD) 3 under hypoxic conditions. Mol Cells 37: 43‐50, 2014.
 187.Lehman JJ, Kelly DP. Gene regulatory mechanisms governing energy metabolism during cardiac hypertrophic growth. Heart Fail Rev 7: 175‐185, 2002.
 188.Leoni F, Zaliani A, Bertolini G, Porro G, Pagani P, Pozzi P, Dona G, Fossati G, Sozzani S, Azam T, Bufler P, Fantuzzi G, Goncharov I, Kim SH, Pomerantz BJ, Reznikov LL, Siegmund B, Dinarello CA, Mascagni P. The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc Natl Acad Sci U S A 99: 2995‐3000, 2002.
 189.Levy DE, Darnell JE, Jr. Stats: Transcriptional control and biological impact. Nat Rev Mol Cell Biol 3: 651‐662, 2002.
 190.Li J, Umar S, Amjedi M, Iorga A, Sharma S, Nadadur RD, Regitz‐Zagrosek V, Eghbali M. New frontiers in heart hypertrophy during pregnancy. Am J Cardiovasc Dis 2: 192‐207, 2012.
 191.Li N, Bian H, Zhang J, Li X, Ji X, Zhang Y. The Th17/Treg imbalance exists in patients with heart failure with normal ejection fraction and heart failure with reduced ejection fraction. Clin Chim Acta 411: 1963‐1968, 2010.
 192.Li Y, Reddy MA, Miao F, Shanmugam N, Yee JK, Hawkins D, Ren B, Natarajan R. Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF‐kappaB‐dependent inflammatory genes. Relevance to diabetes and inflammation. J Biol Chem 283: 26771‐26781, 2008.
 193.Licciardi PV, Karagiannis TC. Regulation of immune responses by histone deacetylase inhibitors. ISRN Hematol 2012: 690901, 2012.
 194.Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti‐Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz‐Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462: 315‐322, 2009.
 195.Liu F, Levin MD, Petrenko NB, Lu MM, Wang T, Yuan LJ, Stout AL, Epstein JA, Patel VV. Histone‐deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin. J Mol Cell Cardiol 45: 715‐723, 2008.
 196.Liu T, Song D, Dong J, Zhu P, Liu J, Liu W, Ma X, Zhao L, Ling S. Current understanding of the pathophysiology of myocardial fibrosis and its quantitative assessment in heart failure. Front Physiol 8: 238, 2017.
 197.Liu YJ, Wang LQ, Predina J, Han RX, Beier UH, Wang LCS, Kapoor V, Bhatti TR, Akimova T, Singhal S, Brindle PK, Cole PA, Albelda SM, Hancock WW. Inhibition of p300 impairs Foxp3(+) T regulatory cell function and promotes antitumor immunity. Nat Med 19: 1173‐1177, 2013.
 198.Luger K, Dechassa ML, Tremethick DJ. New insights into nucleosome and chromatin structure: An ordered state or a disordered affair? Nat Rev Mol Cell Bio 13: 436‐447, 2012.
 199.Ma Y, Iyer RP, Jung M, Czubryt MP, Lindsey ML. Cardiac fibroblast activation post‐myocardial infarction: Current knowledge gaps. Trends Pharmacol Sci 38: 448‐458, 2017.
 200.Ma Y, Yabluchanskiy A, Lindsey ML. Neutrophil roles in left ventricular remodeling following myocardial infarction. Fibrogenesis Tissue Repair 6: 11, 2013.
 201.Maeda K, Doi S, Nakashima A, Nagai T, Irifuku T, Ueno T, Masaki T. Inhibition of H3K9 methyltransferase G9a ameliorates methylglyoxal‐induced peritoneal fibrosis. PLoS One 12: e0173706, 2017.
 202.Mann DL. Inflammatory mediators and the failing heart: Past, present, and the foreseeable future. Circ Res 91: 988‐998, 2002.
 203.Mann DL. Innate immunity and the failing heart: The cytokine hypothesis revisited. Circ Res 116: 1254‐1268, 2015.
 204.Mann J, Chu DC, Maxwell A, Oakley F, Zhu NL, Tsukamoto H, Mann DA. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 138: 705‐714, 714 e701‐704, 2010.
 205.Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T. Targeted anticytokine therapy in patients with chronic heart failure: Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109: 1594‐1602, 2004.
 206.Mann J, Oakley F, Akiboye F, Elsharkawy A, Thorne AW, Mann DA. Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: Implications for wound healing and fibrogenesis. Cell Death Differ 14: 275‐285, 2007.
 207.Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25: 677‐686, 2004.
 208.Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: Tumor‐associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23: 549‐555, 2002.
 209.Marmorstein R. Structure and function of histone acetyltransferases. Cell Mol Life Sci 58: 693‐703, 2001.
 210.Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep 6: 13, 2014.
 211.Martinez SR, Gay MS, Zhang LB. Epigenetic mechanisms in heart development and disease. Drug Discov Today 20: 799‐811, 2015.
 212.Matouk CC, Marsden PA. Epigenetic regulation of vascular endothelial gene expression. Circ Res 102: 873‐887, 2008.
 213.Matsushima S, Sadoshima J. The role of sirtuins in cardiac disease. Am J Physiol‐Heart C 309: H1375‐H1389, 2015.
 214.Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D'Souza C, Fouse SD, Johnson BE, Hong CB, Nielsen C, Zhao YJ, Turecki G, Delaney A, Varhol R, Thiessen N, Shchors K, Heine VM, Rowitch DH, Xing XY, Fiore C, Schillebeeckx M, Jones SJM, Haussler D, Marra MA, Hirst M, Wang T, Costello JF. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466: 253‐U131, 2010.
 215.McDonnell F, Irnaten M, Clark AF, O'Brien CJ, Wallace DM. Hypoxia‐induced changes in DNA methylation alter RASAL1 and TGFbeta1 expression in human trabecular meshwork cells. PLoS One 11: e0153354, 2016.
 216.McKinsey TA. Targeting inflammation in heart failure with histone deacetylase inhibitors. Mol Med 17: 434‐441, 2011.
 217.Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science 335: 936‐941, 2012.
 218.Miceli MC, Parnes JR. Role of CD4 and CD8 in T cell activation and differentiation. Adv Immunol 53: 59‐122, 1993.
 219.Miyamoto S, Kawamura T, Morimoto T, Ono K, Wada H, Kawase Y, Matsumori A, Nishio R, Kita T, Hasegawa K. Histone acetyltransferase activity of p300 is required for the promotion of left ventricular remodeling after myocardial infarction in adult mice in vivo. Circulation 113: 679‐690, 2006.
 220.Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 131: 550‐559, 2014.
 221.Mohn F, Schubeler D. Genetics and epigenetics: Stability and plasticity during cellular differentiation. Trends Genet 25: 129‐136, 2009.
 222.Montgomery RL, Davis CA, Potthoff MJ, Haberland M, Fielitz J, Qi X, Hill JA, Richardson JA, Olson EN. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev 21: 1790‐1802, 2007.
 223.Montgomery RL, Potthoff MJ, Haberland M, Qi X, Matsuzaki S, Humphries KM, Richardson JA, Bassel‐Duby R, Olson EN. Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J Clin Invest 118: 3588‐3597, 2008.
 224.Moore‐Morris T, Guimaraes‐Camboa N, Banerjee I, Zambon AC, Kisseleva T, Velayoudon A, Stallcup WB, Gu Y, Dalton ND, Cedenilla M, Gomez‐Amaro R, Zhou B, Brenner DA, Peterson KL, Chen J, Evans SM. Resident fibroblast lineages mediate pressure overload‐induced cardiac fibrosis. J Clin Invest 124: 2921‐2934, 2014.
 225.Morimoto T, Sunagawa Y, Fujita M, Hasegawa K. Novel heart failure therapy targeting transcriptional pathway in cardiomyocytes by a natural compound, curcumin. Circ J 74: 1059‐1066, 2010.
 226.Morimoto T, Sunagawa Y, Kawamura T, Takaya T, Wada H, Nagasawa A, Komeda M, Fujita M, Shimatsu A, Kita T, Hasegawa K. The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats. J Clin Invest 118: 868‐878, 2008.
 227.Morrell NW, Bloch DB, ten Dijke P, Goumans MJTH, Hata A, Smith J, Yu PB, Bloch KD. Targeting BMP signalling in cardiovascular disease and anaemia. Nat Rev Cardiol 13: 106‐120, 2016.
 228.Mottamal M, Zheng SL, Huang TL, Wang GD. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules 20: 3898‐3941, 2015.
 229.Movassagh M, Choy MK, Goddard M, Bennett MR, Down TA, Foo RSY. Differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure. PLoS One 5: e8564, 2010.
 230.Movassagh M, Choy MK, Knowles DA, Cordeddu L, Haider S, Down T, Siggens L, Vujic A, Simeoni I, Penkett C, Goddard M, Lio P, Bennett MR, Foo RSY. Distinct epigenomic features in end‐stage failing human hearts. Circulation 124: 2411‐2422, 2011.
 231.Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després J‐P, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB. Heart disease and stroke statistics—2016 update. Circulation 133: e38‐e360, 2016.
 232.Muka T, Koromani F, Portilla E, O'Connor A, Bramer WM, Troup J, Chowdhury R, Dehghan A, Franco OH. The role of epigenetic modifications in cardiovascular disease: A systematic review. Int J Cardiol 212: 174‐183, 2016.
 233.Mukasa R, Balasubramani A, Lee YK, Whitley SK, Weaver BT, Shibata Y, Crawford GE, Hatton RD, Weaver CT. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity 32: 616‐627, 2010.
 234.Mullican SE, Gaddis CA, Alenghat T, Nair MG, Giacomin PR, Everett LJ, Feng D, Steger DJ, Schug J, Artis D, Lazar MA. Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Gene Dev 25: 2480‐2488, 2011.
 235.Myers JM, Cooper LT, Kem DC, Stavrakis S, Kosanke SD, Shevach EM, Fairweather D, Stoner JA, Cox CJ, Cunningham MW. Cardiac myosin‐Th17 responses promote heart failure in human myocarditis. Jci Insight 1: 2016.
 236.Napoli C, Grimaldi V, De Pascale MR, Sommese L, Infante T, Soricelli A. Novel epigenetic‐based therapies useful in cardiovascular medicine. World J Cardiol 8: 211‐219, 2016.
 237.Navada SC, Steinmann J, Lubbert M, Silverman LR. Clinical development of demethylating agents in hematology. J Clin Invest 124: 40‐46, 2014.
 238.Nencioni A, Beck J, Werth D, Grunebach F, Patrone F, Ballestrero A, Brossart P. Histone deacetylase inhibitors affect dendritic cell differentiation and immunogenicity. Clin Cancer Res 13: 3933‐3941, 2007.
 239.Netea MG, Quintin J, van der Meer JWM. Trained immunity: A memory for innate host defense. Cell Host Microbe 9: 355‐361, 2011.
 240.Nevers T, Salvador AM, Grodecki‐Pena A, Knapp A, Velazquez F, Aronovitz M, Kapur NK, Karas RH, Blanton RM, Alcaide P. Left ventricular T‐cell recruitment contributes to the pathogenesis of heart failure. Circ‐Heart Fail 8: 776‐U160, 2015.
 241.Neveu WA, Mills ST, Staitieh BS, Sueblinvong V. TGF‐beta1 epigenetically modifies Thy‐1 expression in primary lung fibroblasts. Am J Physiol Cell Physiol 309: C616‐C626, 2015.
 242.Niki T, Rombouts K, De Bleser P, De Smet K, Rogiers V, Schuppan D, Yoshida M, Gabbiani G, Geerts A. A histone deacetylase inhibitor, trichostatin A, suppresses myofibroblastic differentiation of rat hepatic stellate cells in primary culture. Hepatology 29: 858‐867, 1999.
 243.Nuhrenberg TG, Hammann N, Schnick T, Preissl S, Witten A, Stoll M, Gilsbach R, Neumann FJ, Hein L. Cardiac myocyte de novo DNA methyltransferases 3a/3b are dispensable for cardiac function and remodeling after chronic pressure overload in mice. PLoS One 10: e0131019, 2015.
 244.Nural‐Guvener H, Zakharova L, Feehery L, Sljukic S, Gaballa M. Anti‐fibrotic effects of class I HDAC inhibitor, Mocetinostat is associated with IL‐6/Stat3 signaling in ischemic heart failure. Int J Mol Sci 16: 11482‐11499, 2015.
 245.Nural‐Guvener HF, Zakharova L, Nimlos J, Popovic S, Mastroeni D, Gaballa MA. HDAC class I inhibitor, Mocetinostat, reverses cardiac fibrosis in heart failure and diminishes CD90+ cardiac myofibroblast activation. Fibrogenesis Tissue Repair 7: 10, 2014.
 246.Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247‐257, 1999.
 247.Olson EN. A decade of discoveries in cardiac biology. Nat Med 10: 467‐474, 2004.
 248.Ooi JYY, Tuano NK, Rafehi H, Gao XM, Ziemann M, Du XJ, El‐Osta A. HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes. Epigenetics‐Us 10: 418‐430, 2015.
 249.Ossenkoppele GJ, Lowenberg B, Zachee P, Vey N, Breems D, Van de Loosdrecht AA, Davidson AH, Wells G, Needham L, Bawden L, Toal M, Hooftman L, Debnam PM. A phase I first‐in‐human study with tefinostat ‐ a monocyte/macrophage targeted histone deacetylase inhibitor ‐ in patients with advanced haematological malignancies. Brit J Haematol 162: 191‐201, 2013.
 250.Ostuni R, Piccolo V, Barozzi I, Polletti S, Termanini A, Bonifacio S, Curina A, Prosperini E, Ghisletti S, Natoli G. Latent enhancers activated by stimulation in differentiated cells. Cell 152: 157‐171, 2013.
 251.Pacis A, Tailleux L, Morin AM, Lambourne J, MacIsaac JL, Yotova V, Dumaine A, Danckaert A, Luca F, Grenier JC, Hansen KD, Gicque B, Yu M, Pai A, He C, Tung J, Pastinen T, Kobor MS, Pique‐Regi R, Gilad Y, Barreiro LB. Bacterial infection remodels the DNA methylation landscape of human dendritic cells. Genome Res 25: 1801‐1811, 2015.
 252.Papait R, Cattaneo P, Kunderfranco P, Greco C, Carullo P, Guffanti A, Vigano V, Stirparo GG, Latronico MV, Hasenfuss G, Chen J, Condorelli G. Genome‐wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy. Proc Natl Acad Sci U S A 110: 20164‐20169, 2013.
 253.Patel SR, Kim D, Levitan I, Dressler GR. The BRCT‐domain containing protein PTIP links PAX2 to a histone H3, lysine 4 methyltransferase complex. Dev Cell 13: 580‐592, 2007.
 254.Perugorria MJ, Wilson CL, Zeybel M, Walsh M, Amin S, Robinson S, White SA, Burt AD, Oakley F, Tsukamoto H, Mann DA, Mann J. Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. Hepatology 56: 1129‐1139, 2012.
 255.Pfaffeneder T, Spada F, Wagner M, Brandmayr C, Laube SK, Eisen D, Truss M, Steinbacher J, Hackner B, Kotljarova O, Schuermann D, Michalakis S, Kosmatchev O, Schiesser S, Steigenberger B, Raddaoui N, Kashiwazaki G, Muller U, Spruijt CG, Vermeulen M, Leonhardt H, Schar P, Muller M, Carell T. Tet oxidizes thymine to 5‐hydroxymethyluracil in mouse embryonic stem cell DNA. Nat Chem Biol 10: 574‐581, 2014.
 256.Phan SH. Biology of fibroblasts and myofibroblasts. Proc Am Thorac Soc 5: 334‐337, 2008.
 257.Pinto AR, Godwin JW, Rosenthal NA. Macrophages in cardiac homeostasis, injury responses and progenitor cell mobilisation. Stem Cell Res 13: 705‐714, 2014.
 258.Pinto AR, Ilinykh A, Ivey MJ, Kuwabara JT, D'Antoni ML, Debuque R, Chandran A, Wang LN, Arora K, Rosenthal NA, Tallquist MD. Revisiting cardiac cellular composition. Circ Res 118: 400‐409, 2016.
 259.Poralla L, Stroh T, Erben U, Sittig M, Liebig S, Siegmund B, Glauben R. Histone deacetylase 5 regulates the inflammatory response of macrophages. J Cell Mol Med 19: 2162‐2171, 2015.
 260.Porcheray F, Viaud S, Rimaniol AC, Leone C, Samah B, Dereuddre‐Bosquet N, Dormont D, Gras G. Macrophage activation switching: An asset for the resolution of inflammation. Clin Exp Immunol 142: 481‐489, 2005.
 261.Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 28: 1057‐1068, 2010.
 262.Porter KE, Turner NA. Cardiac fibroblasts: At the heart of myocardial remodeling. Pharmacol Ther 123: 255‐278, 2009.
 263.Prakash S, Agrawal S, Cao J‐n, Gupta S, Agrawal A. Impaired secretion of interferons by dendritic cells from aged subjects to influenza. Age 35: 1785‐1797, 2012.
 264.Preissl S, Schwaderer M, Raulf A, Hesse M, Gruning BA, Kobele C, Backofen R, Fleischmann BK, Hein L, Gilsbach R. Deciphering the epigenetic code of cardiac myocyte transcription. Circ Res 117: 413‐423, 2015.
 265.Qiao Y, Giannopoulou EG, Chan CH, Park SH, Gong SC, Chen J, Hu XY, Elemento O, Ivashkiv LB. Synergistic activation of inflammatory cytokine genes by interferon‐gamma‐induced chromatin remodeling and toll‐like receptor signaling. Immunity 39: 454‐469, 2013.
 266.Qin L, Han YP. Epigenetic repression of matrix metalloproteinases in myofibroblastic hepatic stellate cells through histone deacetylases 4: Implication in tissue fibrosis. Am J Pathol 177: 1915‐1928, 2010.
 267.Quintin J, Saeed S, Martens JHA, Giamarellos‐Bourboulis EJ, Ifrim DC, Logie C, Jacobs L, Jansen T, Kullberg BJ, Wijmenga C, Joosten LAB, Xavier RJ, van der Meer JWM, Stunnenberg HG, Netea MG. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12: 223‐232, 2012.
 268.Rada‐Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, Wysocka J. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470: 279, 2011.
 269.Rauch TA, Wu X, Zhong X, Riggs AD, Pfeifer GP. A human B cell methylome at 100‐base pair resolution. Proc Natl Acad Sci U S A 106: 671‐678, 2009.
 270.Ravi PR, Vats R, Balija J, Adapa SPN, Aditya N. Modified pullulan nanoparticles for oral delivery of lopinavir: Formulation and pharmacokinetic evaluation. Carbohyd Polym 110: 320‐328, 2014.
 271.Reddy P, Sun Y, Toubai T, Duran‐Struuck R, Clouthier SG, Weisiger E, Maeda Y, Tawara I, Krijanovski O, Gatza E, Liu C, Malter C, Mascagni P, Dinarello CA, Ferrara JL. Histone deacetylase inhibition modulates indoleamine 2,3‐dioxygenase‐dependent DC functions and regulates experimental graft‐versus‐host disease in mice. J Clin Invest 118: 2562‐2573, 2008.
 272.Rimbaud S, Ruiz M, Piquereau J, Mateo P, Fortin D, Veksler V, Garnier A, Ventura‐Clapier R. Resveratrol improves survival, hemodynamics and energetics in a rat model of hypertension leading to heart failure. PLoS One 6: e26391, 2011.
 273.Robinson CM, Neary R, Levendale A, Watson CJ, Baugh JA. Hypoxia‐induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy‐1 promoter methylation and the development of a pro‐fibrotic phenotype. Resp Res 13: 74, 2012.
 274.Rodriguez R, Miller KM. Unravelling the genomic targets of small molecules using high‐throughput sequencing. Nat Rev Genet 15: 783‐796, 2014.
 275.Rombouts K, Niki T, Greenwel P, Vandermonde A, Wielant A, Hellemans K, De Bleser P, Yoshida M, Schuppan D, Rojkind M, Geerts A. Trichostatin A, a histone deacetylase inhibitor, suppresses collagen synthesis and prevents TGF‐beta(1)‐induced fibrogenesis in skin fibroblasts. Exp Cell Res 278: 184‐197, 2002.
 276.Ronnerblad M, Andersson R, Olofsson T, Douagi I, Karimi M, Lehmann S, Hoof I, de Hoon M, Itoh M, Nagao‐Sato S, Kawaji H, Lassmann T, Carninci P, Hayashizaki Y, Forrest AR, Sandelin A, Ekwall K, Arner E, Lennartsson A, and consortium F. Analysis of the DNA methylome and transcriptome in granulopoiesis reveals timed changes and dynamic enhancer methylation. Blood 123: e79‐89, 2014.
 277.Rubart M, Field LJ. Cardiac regeneration: repopulating the heart. Annu Rev Physiol 68: 29‐49, 2006.
 278.Rudra D, deRoos P, Chaudhry A, Niec RE, Arvey A, Samstein RM, Leslie C, Shaffer SA, Goodlett DR, Rudensky AY. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol 13: 1010‐1019, 2012.
 279.Russell SB, Russell JD, Trupin KM, Gayden AE, Opalenik SR, Nanney LB, Broquist AH, Raju L, Williams SM. Epigenetically altered wound healing in keloid fibroblasts. J Invest Dermatol 130: 2489‐2496, 2010.
 280.Saccani S, Natoli G. Dynamic changes in histone H3 Lys 9 methylation occurring at tightly regulated inducible inflammatory genes. Genes Dev 16: 2219‐2224, 2002.
 281.Saeed S, Quintin J, Kerstens HHD, Rao NA, Aghajanirefah A, Matarese F, Cheng SC, Ratter J, Berentsen K, van der Ent MA, Sharifi N, Janssen‐Megens EM, Ter Huurne M, Mandoli A, van Schaik T, Ng A, Burden F, Downes K, Frontini M, Kumar V, Giamarellos‐Bourboulis EJ, Ouwehand WH, van der Meer JWM, Joosten LAB, Wijmenga C, Martens JHA, Xavier RJ, Logie C, Netea MG, Stunnenberg HG. Epigenetic programming of monocyte‐to‐macrophage differentiation and trained innate immunity. Science 345: 1578, 2014.
 282.Salminen A, Kaarniranta K, Kauppinen A. Hypoxia‐inducible histone lysine demethylases: Impact on the aging process and age‐related diseases. Aging Dis 7: 180‐200, 2016.
 283.Sanders YY, Kumbla P, Hagood JS. Enhanced myofibroblastic differentiation and survival in Thy‐1(−) lung fibroblasts. Am J Respir Cell Mol Biol 36: 226‐235, 2007.
 284.Sanders YY, Tollefsbol TO, Varisco BM, Hagood JS. Epigenetic regulation of thy‐1 by histone deacetylase inhibitor in rat lung fibroblasts. Am J Respir Cell Mol Biol 45: 16‐23, 2011.
 285.Santiago JJ, Dangerfield AL, Rattan SG, Bathe KL, Cunnington RH, Raizman JE, Bedosky KM, Freed DH, Kardami E, Dixon IMC. Cardiac fibroblast to myofibroblast differentiation in vivo and in vitro: Expression of focal adhesion components in neonatal and adult rat ventricular myofibroblasts. Dev Dynam 239: 1573‐1584, 2010.
 286.Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T, Honma K, Matsuyama T, Yui K, Tsujimura T, Standley DM, Nakanishi K, Nakai K, Akira S. The Jmjd3‐Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 11: 936‐U989, 2010.
 287.Saxonov S, Berg P, Brutlag DL. A genome‐wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci U S A 103: 1412‐1417, 2006.
 288.Schmidl C, Klug M, Boeld TJ, Andreesen R, Hoffmann P, Edinger M, Rehli M. Lineage‐specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 19: 1165‐1174, 2009.
 289.Schoenborn JR, Dorschner MO, Sekimata M, Santer DM, Shnyreva M, Fitzpatrick DR, Stamatoyannopoulos JA, Wilson CB. Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon‐gamma. Nat Immunol 8: 732‐742, 2007.
 290.Schotta G, Sengupta R, Kubicek S, Malin S, Kauer M, Callen E, Celeste A, Pagani M, Opravil S, De La Rosa‐Velazquez IA, Espejo A, Bedford MT, Nussenzweig A, Busslinger M, Jenuwein T. A chromatin‐wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev 22: 2048‐2061, 2008.
 291.Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G. Genome regulation by polycomb and trithorax proteins. Cell 128: 735‐745, 2007.
 292.Scott EW, Simon MC, Anastasi J, Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265: 1573‐1577, 1994.
 293.Sellars M, Huh JR, Day K, Issuree PD, Galan C, Gobeil S, Absher D, Green MR, Littman DR. Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages. Nat Immunol 16: 746‐754, 2015.
 294.Sen GL, Reuter JA, Webster DE, Zhu L, Khavari PA. DNMT1 maintains progenitor function in self‐renewing somatic tissue. Nature 463: 563‐U189, 2010.
 295.Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res 250: 273‐283, 1999.
 296.Shakespear MR, Hohenhaus DM, Kelly GM, Kamal NA, Gupta P, Labzin LI, Schroder K, Garceau V, Barbero S, Iyer A, Hume DA, Reid RC, Irvine KM, Fairlie DP, Sweet MJ. Histone deacetylase 7 promotes toll‐like receptor 4‐dependent proinflammatory gene expression in macrophages. J Biol Chem 288: 25362‐25374, 2013.
 297.Shann YJ, Cheng C, Chiao CH, Chen DT, Li PH, Hsu MT. Genome‐wide mapping and characterization of hypomethylated sites in human tissues and breast cancer cell lines. Genome Res 18: 791‐801, 2008.
 298.Sheng W, Qian YY, Wang HJ, Ma XJ, Zhang P, Chen L, Ma D, Huang GY. Association between mRNA levels of DNMT1, DNMT3A, DNMT3B, MBD2 and LINE‐1 methylation status in infants with tetralogy of Fallot. Int J Mol Med 32: 694‐702, 2013.
 299.Sheng W, Wang HJ, Ma XJ, Qian YY, Zhang P, Wu Y, Zheng FY, Chen L, Huang GY, Ma D. LINE‐1 methylation status and its association with tetralogy of fallot in infants. Bmc Med Genomics 5: 20, 2012.
 300.Shi Y, Whetstine JR. Dynamic regulation of histone lysine methylation by demethylases. Mol Cell 25: 1‐14, 2007.
 301.Shinagawa H, Frantz S. Cellular immunity and cardiac remodeling after myocardial infarction: Role of neutrophils, monocytes, and macrophages. Curr Heart Fail Rep 12: 247‐254, 2015.
 302.Shirodkar AV, St Bernard R, Gavryushova A, Kop A, Knight BJ, Yan MS, Man HS, Sud M, Hebbel RP, Oettgen P, Aird WC, Marsden PA. A mechanistic role for DNA methylation in endothelial cell (EC)‐enriched gene expression: Relationship with DNA replication timing. Blood 121: 3531‐3540, 2013.
 303.Smith ZD, Meissner A. DNA methylation: Roles in mammalian development. Nat Rev Genet 14: 204‐220, 2013.
 304.Smolarek I, Wyszko E, Barciszewska AM, Nowak S, Gawronska I, Jablecka A, Barciszewska MZ. Global DNA methylation changes in blood of patients with essential hypertension. Med Sci Monitor 16: Cr149‐Cr155, 2010.
 305.Song W, Tai YT, Tian Z, Hideshima T, Chauhan D, Nanjappa P, Exley MA, Anderson KC, Munshi NC. HDAC inhibition by LBH589 affects the phenotype and function of human myeloid dendritic cells. Leukemia 25: 161‐168, 2011.
 306.Souders CA, Bowers SL, Baudino TA. Cardiac fibroblast: The renaissance cell. Circ Res 105: 1164‐1176, 2009.
 307.Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: Influence on cardiac form and function. Physiol Rev 87: 1285‐1342, 2007.
 308.Stein AB, Goonewardena SN, Jones TA, Prusick PJ, Bazzi AA, Belyavskaya JM, McCoskey MM, Dandar RA. The PTIP‐associated histone methyltransferase complex prevents stress‐induced maladaptive cardiac remodeling. PLoS One 10: e0127839, 2015.
 309.Stein AB, Jones TA, Herron TJ, Patel SR, Day SM, Noujaim SF, Milstein ML, Klos M, Furspan PB, Jalife J, Dressler GR. Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes. J Clin Invest 121: 2641‐2650, 2011.
 310.Stengel KR, Zhao Y, Klus NJ, Kaiser JF, Gordy LE, Joyce S, Hiebert SW, Summers AR. Histone deacetylase 3 is required for efficient T cell development. Mol Cell Biol 35: 3854‐3865, 2015.
 311.Summers AR, Fischer MA, Stengel KR, Zhao Y, Kaiser JF, Wells CE, Hunt A, Bhaskara S, Luzwick JW, Sampathi S, Chen X, Thompson MA, Cortez D, Hiebert SW. HDAC3 is essential for DNA replication in hematopoietic progenitor cells. J Clin Invest 123: 3112‐3123, 2013.
 312.Sun Y, Chin YE, Weisiger E, Malter C, Tawara I, Toubai T, Gatza E, Mascagni P, Dinarello CA, Reddy P. Cutting edge: Negative regulation of dendritic cells through acetylation of the nonhistone protein STAT‐3. J Immunol 182: 5899‐5903, 2009.
 313.Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a‐dependent antioxidant defense mechanisms in mice. J Clin Invest 119: 2758‐2771, 2009.
 314.Sundaresan NR, Pillai VB, Wolfgeher D, Samant S, Vasudevan P, Parekh V, Raghuraman H, Cunningham JM, Gupta M, Gupta MP. The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci Signal 4: ra46, 2011.
 315.Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB, Gupta MP. SIRT3 is a stress‐responsive deacetylase in cardiomyocytes that protects cells from stress‐mediated cell death by deacetylation of Ku70. Mol Cell Biol 28: 6384‐6401, 2008.
 316.Sundaresan NR, Vasudevan P, Zhong L, Kim G, Samant S, Parekh V, Pillai VB, Ravindra PV, Gupta M, Jeevanandam V, Cunningham JM, Deng CX, Lombard DB, Mostoslavsky R, Gupta MP. The sirtuin SIRT6 blocks IGF‐Akt signaling and development of cardiac hypertrophy by targeting c‐Jun. Nat Med 18: 1643‐1650, 2012.
 317.Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: Pathophysiology and therapy. Circulation 101: 2981‐2988, 2000.
 318.Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science 339: 161‐166, 2013.
 319.Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev 79: 215‐262, 1999.
 320.Takawale A, Sakamuri SS, Kassiri Z. Extracellular matrix communication and turnover in cardiac physiology and pathology. Compr Physiol 5: 687‐719, 2015.
 321.Tampe B, Tampe D, Muller CA, Sugimoto H, LeBleu V, Xu XB, Muller GA, Zeisberg EM, Kalluri R, Zeisberg M. Tet3‐mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7‐induced reversal of kidney fibrosis. J Am Soc Nephrol 25: 905‐912, 2014.
 322.Tang T‐T, Ding Y‐J, Liao Y‐H, Yu X, Xiao H, Xie J‐J, Yuan J, Zhou Z‐H, Liao M‐Y, Yao R, Cheng Y, Cheng X. Defective circulating CD4+CD25+Foxp3+CD127low regulatory T‐cells in patients with chronic heart failure. Cell Physiol Biochem 25: 451‐458, 2010.
 323.Tanno M, Kuno A, Yano T, Miura T, Hisahara S, Ishikawa S, Shimamoto K, Horio Y. Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. J Biol Chem 285: 8375‐8382, 2010.
 324.Tao H, Huang C, Yang JJ, Ma TT, Bian EB, Zhang L, Lv XW, Jin Y, Li J. MeCP2 controls the expression of RASAL1 in the hepatic fibrosis in rats. Toxicology 290: 327‐333, 2011.
 325.Tao H, Yang JJ, Chen ZW, Xu SS, Zhou X, Zhan HY, Shi KH. DNMT3A silencing RASSF1A promotes cardiac fibrosis through upregulation of ERK1/2. Toxicology 323: 42‐50, 2014.
 326.Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM, Li B, Turka LA, Olson EN, Greene MI, Wells AD, Hancock WW. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 13: 1299‐1307, 2007.
 327.Testa M, Yeh M, Lee P, Fanelli R, Loperfido F, Berman JW, LeJemtel TH. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J Am Coll Cardiol 28: 964‐971, 1996.
 328.Thandapilly SJ, Wojciechowski P, Behbahani J, Louis XL, Yu LP, Juric D, Kopilas MA, Anderson HD, Netticadan T. Resveratrol prevents the development of pathological cardiac hypertrophy and contractile dysfunction in the SHR without lowering blood pressure. Am J Hypertens 23: 192‐196, 2010.
 329.Trivedi CM, Lu MM, Wang Q, Epstein JA. Transgenic overexpression of Hdac3 in the heart produces increased postnatal cardiac myocyte proliferation but does not induce hypertrophy. J Biol Chem 283: 26484‐26489, 2008.
 330.Trivedi CM, Luo Y, Yin Z, Zhang M, Zhu W, Wang T, Floss T, Goettlicher M, Noppinger PR, Wurst W, Ferrari VA, Abrams CS, Gruber PJ, Epstein JA. Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nat Med 13: 324‐331, 2007.
 331.Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, Braun T, Bober E. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ Res 102: 703‐710, 2008.
 332.van Amerongen MJ, Bou‐Gharios G, Popa E, van Ark J, Petersen AH, van Dam GM, van Luyn MJ, Harmsen MC. Bone marrow‐derived myofibroblasts contribute functionally to scar formation after myocardial infarction. J Pathol 214: 377‐386, 2008.
 333.van Loosdregt J, Coffer PJ. Post‐translational modification networks regulating FOXP3 function. Trends Immunol 35: 368‐378, 2014.
 334.Vento‐Tormo R, Company C, Rodriguez‐Ubreva J, de la Rica L, Urquiza JM, Javierre BM, Sabarinathan R, Luque A, Esteller M, Aran JM, Alvarez‐Errico D, Ballestar E. IL‐4 orchestrates STAT6‐mediated DNA demethylation leading to dendritic cell differentiation. Genome Biol 17: 4, 2016.
 335.Verdone L, Caserta M, Di Mauro E. Role of histone acetylation in the control of gene expression. Biochem Cell Biol 83: 344‐353, 2005.
 336.Volkmar M, Dedeurwaerder S, Cunha DA, Ndlovu MN, Defrance M, Deplus R, Calonne E, Volkmar U, Igoillo‐Esteve M, Naamane N, Del Guerra S, Masini M, Bugliani M, Marchetti P, Cnop M, Eizirik DL, Fuks F. DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. Embo J 31: 1405‐1426, 2012.
 337.Vujic A, Robinson EL, Ito M, Haider S, Ackers‐Johnson M, See K, Methner C, Figg N, Brien P, Roderick HL, Skepper J, Ferguson‐Smith A, Foo RS. Experimental heart failure modelled by the cardiomyocyte‐specific loss of an epigenome modifier, DNMT3B. J Mol Cell Cardiol 82: 174‐183, 2015.
 338.Wagner EJ, Carpenter PB. Understanding the language of Lys36 methylation at histone H3. Nat Rev Mol Cell Bio 13: 115‐126, 2012.
 339.Wallner S, Schroder C, Leitao E, Berulava T, Haak C, Beisser D, Rahmann S, Richter AS, Manke T, Bonisch U, Arrigoni L, Frohler S, Klironomos F, Chen W, Rajewsky N, Muller F, Ebert P, Lengauer T, Barann M, Rosenstiel P, Gasparoni G, Nordstrom K, Walter J, Brors B, Zipprich G, Felder B, Klein‐Hitpass L, Attenberger C, Schmitz G, Horsthemke B. Epigenetic dynamics of monocyte‐to‐macrophage differentiation. Epigenet Chromatin 9: 33, 2016.
 340.Wamstad JA, Alexander JM, Truty RM, Shrikumar A, Li FG, Eilertson KE, Ding HM, Wylie JN, Pico AR, Capra JA, Erwin G, Kattman SJ, Keller GM, Srivastava D, Levine SS, Pollard KS, Holloway AK, Boyer LA, Bruneau BG. Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Cell 151: 206‐220, 2012.
 341.Wang J, Gong L, Tan Y, Hui R, Wang Y. Hypertensive epigenetics: From DNA methylation to microRNAs. J Hum Hypertens 29: 575‐582, 2015.
 342.Wang L, Liu Y, Han R, Beier UH, Bhatti TR, Akimova T, Greene MI, Hiebert SW, Hancock WW. FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3. J Clin Invest 125: 1111‐1123, 2015.
 343.Wang QT. Epigenetic regulation of cardiac development and function by polycomb group and trithorax group proteins. Dev Dynam 241: 1021‐1033, 2012.
 344.Wang XB, Han YD, Sabina S, Cui NH, Zhang S, Liu ZJ, Li C, Zheng F. HDAC9 variant Rs2107595 modifies susceptibility to coronary artery disease and the severity of coronary atherosclerosis in a Chinese Han population. PLoS One 11: e0160449, 2016.
 345.Wang XF, Cao Q, Yu LQ, Shi HD, Xue BZ, Shi H. Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity. Jci Insight 1: e87748, 2016.
 346.Wang Y, Fan PS, Kahaleh B. Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum 54: 2271‐2279, 2006.
 347.Wang YG, Miao X, Liu YC, Li FS, Liu Q, Sun J, Cai L. Dysregulation of histone acetyltransferases and deacetylases in cardiovascular diseases. Oxid Med Cell Longev 2014: 641979, 2014.
 348.Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, Zhao K. Genome‐wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138: 1019‐1031, 2009.
 349.Wang Z, Zhang XJ, Ji YX, Zhang P, Deng KQ, Gong J, Ren S, Wang X, Chen I, Wang H, Gao C, Yokota T, Ang YS, Li S, Cass A, Vondriska TM, Li G, Deb A, Srivastava D, Yang HT, Xiao X, Li H, Wang Y. The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med 22: 1131‐1139, 2016.
 350.Watson CJ, Collier P, Tea I, Neary R, Watson JA, Robinson C, Phelan D, Ledwidge MT, McDonald KM, McCann A, Sharaf O, Baugh JA. Hypoxia‐induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast‐like phenotype. Hum Mol Genet 23: 2176‐2188, 2014.
 351.Watson CJ, Horgan S, Neary R, Glezeva N, Tea I, Corrigan N, McDonald K, Ledwidge M, Baugh J. Epigenetic therapy for the treatment of hypertension‐induced cardiac hypertrophy and fibrosis. J Cardiovasc Pharmacol Ther 21: 127‐137, 2016.
 352.Weeks KL, Avkiran M. Roles and post‐translational regulation of cardiac class IIa histone deacetylase isoforms. J Physiol‐London 593: 1785‐1797, 2015.
 353.Wei JQ, Shehadeh LA, Mitrani JM, Pessanha M, Slepak TI, Webster KA, Bishopric NH. Quantitative control of adaptive cardiac hypertrophy by acetyltransferase p300. Circulation 118: 934‐946, 2008.
 354.Wei L, Vahedi G, Sun HW, Watford WT, Takatori H, Ramos HL, Takahashi H, Liang J, Gutierrez‐Cruz G, Zang CZ, Peng WQ, O'Shea JJ, Kanno Y. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 32: 840‐851, 2010.
 355.Wierda RJ, Goedhart M, van Eggermond MCJA, Muggen AF, Miggelbrink XM, Geutskens SB, van Zwet E, Haasnoot GW, van den Elsen PJ. A role for KMT1c in monocyte to dendritic cell differentiation Epigenetic regulation of monocyte differentiation. Hum Immunol 76: 431‐437, 2015.
 356.Wildner G, Weiss EH, Szots H, Riethmuller G, Schendel DJ. The use of fusion proteins to study HLA‐B27‐specific allorecognition. Mol Immunol 26: 33‐40, 1989.
 357.Willems IE, Havenith MG, De Mey JG, Daemen MJ. The alpha‐smooth muscle actin‐positive cells in healing human myocardial scars. Am J Pathol 145: 868‐875, 1994.
 358.Wilson CB, Rowell E, Sekimata M. Epigenetic control of T‐helper‐cell differentiation. Nat Rev Immunol 9: 91‐105, 2009.
 359.Winders BR, Schwartz RH, Bruniquel D. A distinct region of the murine IFN‐gamma promoter is hypomethylated from early T cell development through mature naive and Th1 cell differentiation, but is hypermethylated in Th2 cells. J Immunol 173: 7377‐7384, 2004.
 360.Wise IA, Charchar FJ. Epigenetic modifications in essential hypertension. Int J Mol Sci 17: 451, 2016.
 361.Wongcharoen W, Phrommintikul A. The protective role of curcumin in cardiovascular diseases. Int J Cardiol 133: 145‐151, 2009.
 362.Wu H, Zhang Y. Reversing DNA methylation: Mechanisms, genomics, and biological functions. Cell 156: 45‐68, 2014.
 363.Xiao DL, Dasgupta C, Chen M, Zhang KL, Buchholz J, Xu ZC, Zhang LB. Inhibition of DNA methylation reverses norepinephrine‐induced cardiac hypertrophy in rats. Cardiovasc Res 101: 373‐382, 2014.
 364.Xie M, Hill JA. HDAC‐dependent ventricular remodeling. Trends Cardiovas Med 23: 229‐235, 2013.
 365.Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: Molecular mechanisms of action. Oncogene 26: 5541‐5552, 2007.
 366.Xu X, Tan X, Tampe B, Nyamsuren G, Liu X, Maier LS, Sossalla S, Kalluri R, Zeisberg M, Hasenfuss G, Zeisberg EM. Epigenetic balance of aberrant Rasal1 promoter methylation and hydroxymethylation regulates cardiac fibrosis. Cardiovasc Res 105: 279‐291, 2015.
 367.Xu XB, Tan XY, Hulshoff MS, Wilhelmi T, Zeisberg M, Zeisberg EM. Hypoxia‐induced endothelial‐mesenchymal transition is associated with RASAL1 promoter hypermethylation in human coronary endothelial cells. FEBS Lett 590: 1222‐1233, 2016.
 368.Xu XJ, Su SY, Barnes VA, De Miguel C, Pollock J, Ownby D, Shi HD, Zhu HD, Snieder H, Wang XL. A genome‐wide methylation study on obesity differential variability and differential methylation. Epigenetics‐Us 8: 522‐533, 2013.
 369.Xu Z, Tong Q, Zhang Z, Wang S, Zheng Y, Liu Q, Qian L, Chen SY, Sun J, Cai L. Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5‐ERK1/2 pathway. Clin Sci (Lond) 2017.
 370.Yan AT, Yan RT, Cushman M, Redheuil A, Tracy RP, Arnett DK, Rosen BD, McClelland RL, Bluemke DA, Lima JA. Relationship of interleukin‐6 with regional and global left‐ventricular function in asymptomatic individuals without clinical cardiovascular disease: insights from the Multi‐Ethnic Study of Atherosclerosis. Eur Heart J 31: 875‐882, 2010.
 371.Yan B, Xie S, Liu Z, Ran J, Li Y, Wang J, Yang Y, Zhou J, Li D, Liu M. HDAC6 deacetylase activity is critical for lipopolysaccharide‐induced activation of macrophages. PLoS One 9: e110718, 2014.
 372.Yan MS, Marsden PA. Epigenetics in the vascular endothelium: Looking from a different perspective in the epigenomics era. Arterioscler Thromb Vasc Biol 35: 2297‐2306, 2015.
 373.Yan Q, Sun L, Zhu Z, Wang L, Li S, Ye RD. Jmjd3‐mediated epigenetic regulation of inflammatory cytokine gene expression in serum amyloid A‐stimulated macrophages. Cell Signal 26: 1783‐1791, 2014.
 374.Yanazume T, Hasegawa K, Morimoto T, Kawamura T, Wada H, Matsumori A, Kawase Y, Hirai M, Kita T. Cardiac p300 is involved in myocyte growth with decompensated heart failure. Mol Cell Biol 23: 3593‐3606, 2003.
 375.Yang BH, Floess S, Hagemann S, Deyneko IV, Groebe L, Pezoldt J, Sparwasser T, Lochner M, Huehn J. Development of a unique epigenetic signature during in vivo Th17 differentiation. Nucleic Acids Res 43: 1537‐1548, 2015.
 376.Yang J, Ledaki I, Turley H, Gatter KC, Montero JC, Li JL, Harris AL. Role of hypoxia‐inducible factors in epigenetic regulation via histone demethylases. Ann N Y Acad Sci 1177: 185‐197, 2009.
 377.Yang JJ, Tao H, Huang C, Shi KH, Ma TT, Bian EB, Zhang L, Liu LP, Hu W, Lv XW, Li J. DNA methylation and MeCP2 regulation of PTCH1 expression during rats hepatic fibrosis. Cell Signal 25: 1202‐1211, 2013.
 378.Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 26: 577‐590, 2014.
 379.Yang XS, Wang XF, Liu DX, Yu LQ, Xue BZ, Shi H. Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b. Mol Endocrinol 28: 565‐574, 2014.
 380.Yao TP, Oh SP, Fuchs M, Zhou ND, Ch'ng LE, Newsome D, Bronson RT, Li E, Livingston DM, Eckner R. Gene dosage‐dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell 93: 361‐372, 1998.
 381.Yu J, Qiu Y, Yang J, Bian S, Chen G, Deng M, Kang H, Huang L. DNMT1‐PPARgamma pathway in macrophages regulates chronic inflammation and atherosclerosis development in mice. Sci Rep 6: 30053, 2016.
 382.Yu M, Hon GC, Szulwach KE, Song CX, Zhang L, Kim A, Li X, Dai Q, Shen Y, Park B, Min JH, Jin P, Ren B, He C. Base‐resolution analysis of 5‐hydroxymethylcytosine in the mammalian genome. Cell 149: 1368‐1380, 2012.
 383.Zabkiewicz J, Gilmour M, Hills R, Vyas P, Bone E, Davidson A, Burnett A, Knapper S. The targeted histone deacetylase inhibitor tefinostat (CHR‐2845) shows selective in vitro efficacy in monocytoid‐lineage leukaemias. Oncotarget 7: 16650‐16662, 2016.
 384.Zaidi S, Choi M, Wakimoto H, Ma LJ, Jiang JM, Overton JD, Romano‐Adesman A, Bjornson RD, Breitbart RE, Brown KK, Carriero NJ, Cheung YH, Deanfield J, DePalma S, Fakhro KA, Glessner J, Hakonarson H, Italia MJ, Kaltman JR, Kaski J, Kim R, Kline JK, Lee T, Leipzig J, Lopez A, Mane SM, Mitchell LE, Newburger JW, Parfenov M, Pe'er I, Porter G, Roberts AE, Sachidanandam R, Sanders SJ, Seiden HS, State MW, Subramanian S, Tikhonova IR, Wang W, Warburton D, White PS, Williams IA, Zhao HY, Seidman JG, Brueckner M, Chung WK, Gelb BD, Goldmuntz E, Seidman CE, Lifton RP. De novo mutations in histone‐modifying genes in congenital heart disease. Nature 498: 220‐223, 2013.
 385.Zeybel M, Luli S, Sabater L, Hardy T, Oakley F, Leslie J, Page A, Moran Salvador E, Sharkey V, Tsukamoto H, Chu DCK, Singh US, Ponzoni M, Perri P, Di Paolo D, Mendivil EJ, Mann J, Mann DA. A proof‐of‐concept for epigenetic therapy of tissue fibrosis: Inhibition of liver fibrosis progression by 3‐deazaneplanocin A. Mol Ther 25: 218‐231, 2017.
 386.Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN. Class II histone deacetylases act as signal‐responsive repressors of cardiac hypertrophy. Cell 110: 479‐488, 2002.
 387.Zhang LX, Zhao Y, Cheng G, Guo TL, Chin YE, Liu PY, Zhao TC. Targeted deletion of NF‐κB p50 diminishes the cardioprotection of histone deacetylase inhibition. Am J Physiol Heart Circ Physiol 298: H2154‐H2163, 2010.
 388.Zhang QJ, Chen HZ, Wang L, Liu DP, Hill JA, Liu ZP. The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J Clin Invest 121: 2447‐2456, 2011.
 389.Zhang X, Ulm A, Somineni HK, Oh S, Weirauch MT, Zhang HX, Chen XT, Lehn MA, Janssen EM, Ji H. DNA methylation dynamics during ex vivo differentiation and maturation of human dendritic cells. Epigenet Chromatin 7: 21, 2014.
 390.Zhang Y, Zeng CY. Role of DNA methylation in cardiovascular diseases. Clin Exp Hypertens 38: 261‐267, 2016.
 391.Zhu J, Paul WE. CD4 T cells: Fates, functions, and faults. Blood 112: 1557‐1569, 2008.
 392.Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol 28: 445‐489, 2010.
 393.Zhu W, Trivedi CM, Zhou D, Yuan L, Lu MM, Epstein JA. Inpp5f is a polyphosphoinositide phosphatase that regulates cardiac hypertrophic responsiveness. Circ Res 105: 1240‐1247, 2009.
 394.Zhu ZF, Li JJ, Liu J, Tang TT, Ding YJ, Liao YH, Cheng X, Wang X. Circulating Th17 cells are not elevated in patients with chronic heart failure. Scand Cardiovasc J 46: 295‐300, 2012.
 395.Ziegler SF. FOXP3: Of mice and men. Annu Rev Immunol 24: 209‐226, 2006.
 396.Zilbauer M, Rayner TF, Clark C, Coffey AJ, Joyce CJ, Palta P, Palotie A, Lyons PA, Smith KG. Genome‐wide methylation analyses of primary human leukocyte subsets identifies functionally important cell‐type‐specific hypomethylated regions. Blood 122: e52‐60, 2013.
 397.Ziller MJ, Gu HC, Muller F, Donaghey J, Tsai LTY, Kohlbacher O, De Jager PL, Rosen ED, Bennett DA, Bernstein BE, Gnirke A, Meissner A. Charting a dynamic DNA methylation landscape of the human genome. Nature 500: 477‐481, 2013.
 398.Zlatanova J, Leuba SH, van Holde K. Chromatin structure revisited. Crit Rev Eukaryot Gene Expr 9: 245‐255, 1999.
 399.Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, Litsa D, Bellucci R, Raderschall E, Canning C, Soiffer RJ, Frank DA, Ritz J. IL‐2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT‐dependent mechanism and induces the expansion of these cells in vivo. Blood 108: 1571‐1579, 2006.

Teaching Material

A. Russell-Hallinan, C. J. Watson, J. A. Baugh. Epigenetics of Aberrant Cardiac Wound Healing. Compr Physiol. 8: 2018, 451-491.

Didactic Synopsis

Cardiac remodeling is a crucial feature of myocardial responses to injury. Epigenetic alterations and regulation of this multifactorial process are at the forefront of cardiac remodeling research, including the delineating of cell-type specific contributions. This comprehensive review will support undergraduate and postgraduate teaching of concepts relating to the role of epigenetics in dictating inflammatory, fibrotic, and hypertrophic responses in the context of cardiac injury.

Major Teaching Points:

  1. Understanding wound healing responses of both resident cardiac cells and infiltrating inflammatory cells, in pathological settings such as myocardial infarction and pressure overload, is necessary to appreciate the complex pathophysiology that leads to the development of heart failure.
  2. Epigenetic mechanisms such as DNA methylation and posttranslational modifications (acetylation and methylation) of histone tails are important regulators of gene expression and are now considered to be involved in promoting abnormal cardiac wound healing through, extracellular matrix deposition, myocyte hypertrophy, and inflammatory mediator release.
  3. Epigenetic mechanisms critically regulate cellular phenotype and function:
    1. Alterations in DNA methylation (e.g., DNMT3 enzymes) and histone modifications (e.g., HDAC2) can influence the hypertrophic response in postmitotic cardiomyocytes.
    2. Increased DNA methylation in cardiac fibroblasts is associated with sustained activation and extracellular matrix deposition.
    3. Immune cell phenotype, cytokine release, and immune response (trained immunity vs. immunotolerance) are regulated by both DNA methylation and histone modifications.
  4. Advancements in therapeutic targeting or manipulation of the epigenetic machinery in cells implicated in aberrant cardiac remodeling may yield novel treatment strategies in the future management of cardiac diseases including heart failure.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: This illustrated figure demonstrates that various types of injury to the heart can drive epigenetic changes in cardiomyocytes, fibroblasts, and immune cells. These epigenetic changes can result in the acquisition of aberrant phenotypes which drive pathological remodeling in the heart which ultimately leads to the development of heart failure.

Figure 2. Teaching points: This illustrated figure highlights the regulation of gene expression by DNA methylation (gene repression) and demethylation (gene activation) at the promoter region of a gene.

Figure 3. Teaching points: This illustrated figure facilitates understanding of gene regulation by modifications of the amino-terminal tails of histone proteins, focusing on specifically the modifications acetylation and methylation. It also highlights the active and repressive histone marks that are associated with active gene expression or gene silencing.


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Article Title: Epigenetics of Aberrant Cardiac Wound Healing
 

How to Cite

Adam Russell‐Hallinan, Chris J. Watson, John A. Baugh. Epigenetics of Aberrant Cardiac Wound Healing. Compr Physiol 2018, 8: 451-491. doi: 10.1002/cphy.c170029