title: Epigenetic Therapy for the Treatment of Hypertension-Induced Cardiac Hypertrophy and Fibrosis.
abstract: BACKGROUND
  The development of heart failure is associated with changes in the size, shape, and structure of the heart that has a negative impact on cardiac function. These pathological changes involve excessive extracellular matrix deposition within the myocardial interstitium and myocyte hypertrophy. Alterations in fibroblast phenotype and myocyte activity are associated with reprogramming of gene transcriptional profiles that likely requires epigenetic alterations in chromatin structure. The aim of our work was to investigate the potential of a currently licensed anticancer epigenetic modifier as a treatment option for cardiac diseases associated with hypertension-induced cardiac hypertrophy and fibrosis.
  
  
  RESULTS
  The effects of DNA methylation inhibition with 5-azacytidine (5-aza) were examined in a human primary fibroblast cell line and in a spontaneously hypertensive rat (SHR) model. The results from this work allude to novel in vivo antifibrotic and antihypertrophic actions of 5-aza. Administration of the DNA methylation inhibitor significantly improved several echocardiographic parameters associated with hypertrophy and diastolic dysfunction. Myocardial collagen levels and myocyte size were reduced in 5-aza-treated SHRs. These findings are supported by beneficial in vitro effects in cardiac fibroblasts. Collagen I, collagen III, and α-smooth muscle actin were reduced in a human ventricular cardiac fibroblast cell line treated with 5-aza.
  
  
  CONCLUSIONS
  These findings suggest a role for epigenetic modifications in contributing to the profibrotic and hypertrophic changes evident during disease progression. Therapeutic intervention with 5-aza demonstrated favorable effects highlighting the potential use of this epigenetic modifier as a treatment option for cardiac pathologies associated with hypertrophy and fibrosis.
authors.affiliation: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland chris.watson@ucd.ie.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Watson
authors.affiliation: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Stephen
authors.initials: S
authors.lastname: Horgan
authors.affiliation: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Roisin
authors.initials: R
authors.lastname: Neary
authors.affiliation: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Glezeva
authors.affiliation: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Isaac
authors.initials: I
authors.lastname: Tea
authors.affiliation: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Niamh
authors.initials: N
authors.lastname: Corrigan
authors.affiliation: Chronic Cardiovascular Disease Management Unit, St Vincent's Healthcare Group/St Michael's Hospital, Dublin, Ireland.
authors.forename: Ken
authors.initials: K
authors.lastname: McDonald
authors.affiliation: Chronic Cardiovascular Disease Management Unit, St Vincent's Healthcare Group/St Michael's Hospital, Dublin, Ireland.
authors.forename: Mark
authors.initials: M
authors.lastname: Ledwidge
authors.affiliation: School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: Baugh
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects; D000099163:Myosin Binding Protein C
chemical_list: D000199:Actins; D001374:Azacitidine; D002352:Carrier Proteins; D024042:Collagen Type I; D024061:Collagen Type III; D015254:DNA Modification Methylases; D004791:Enzyme Inhibitors; D053773:Transforming Growth Factor beta1; D000099163:Myosin Binding Protein C; C541116:ACTA2 protein, human; C508960:TGFB1 protein, human
keywords: 5-azacytidine; DNA methylation; cardiac fibrosis; epigenetics; hypertension; hypertrophy