title: Transplantation of Epigenetically Modified Adult Cardiac c-Kit+ Cells Retards Remodeling and Improves Cardiac Function in Ischemic Heart Failure Model.
abstract: Cardiac c-Kit+ cells have a modest cardiogenic potential that could limit their efficacy in heart disease treatment. The present study was designed to augment the cardiogenic potential of cardiac c-Kit+ cells through class I histone deacetylase (HDAC) inhibition and evaluate their therapeutic potency in the chronic heart failure (CHF) animal model. Myocardial infarction (MI) was created by coronary artery occlusion in rats. c-Kit+ cells were treated with mocetinostat (MOCE), a specific class I HDAC inhibitor. At 3 weeks after MI, CHF animals were retrogradely infused with untreated (control) or MOCE-treated c-Kit+ cells (MOCE/c-Kit+ cells) and evaluated at 3 weeks after cell infusion. We found that class I HDAC inhibition in c-Kit+ cells elevated the level of acetylated histone H3 (AcH3) and increased AcH3 levels in the promoter regions of pluripotent and cardiac-specific genes. Epigenetic changes were accompanied by increased expression of cardiac-specific markers. Transplantation of CHF rats with either control or MOCE/c-Kit+ cells resulted in an improvement in cardiac function, retardation of CHF remodeling made evident by increased vascularization and scar size, and cardiomyocyte hypertrophy reduction. Compared with CHF infused with control cells, infusion of MOCE/c-Kit+ cells resulted in a further reduction in left ventricle end-diastolic pressure and total collagen and an increase in interleukin-6 expression. The low engraftment of infused cells suggests that paracrine effects might account for the beneficial effects of c-Kit+ cells in CHF. In conclusion, selective inhibition of class I HDACs induced expression of cardiac markers in c-Kit+ cells and partially augmented the efficacy of these cells for CHF repair.
  
  
  CONCLUSIONS
  The study has shown that selective class 1 histone deacetylase inhibition is sufficient to redirect c-Kit+ cells toward a cardiac fate. Epigenetically modified c-Kit+ cells improved contractile function and retarded remodeling of the congestive heart failure heart. This study provides new insights into the efficacy of cardiac c-Kit+ cells in the ischemic heart failure model.
authors.affiliation: Center for Cardiovascular Research, Banner Sun Health Research Institute, Sun City, Arizona, USA.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Zakharova
authors.affiliation: Center for Cardiovascular Research, Banner Sun Health Research Institute, Sun City, Arizona, USA.
authors.forename: Hikmet
authors.initials: H
authors.lastname: Nural-Guvener
authors.affiliation: Center for Cardiovascular Research, Banner Sun Health Research Institute, Sun City, Arizona, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Feehery
authors.affiliation: Center for Cardiovascular Research, Banner Sun Health Research Institute, Sun City, Arizona, USA.
authors.forename: Snjezana
authors.initials: S
authors.lastname: Popovic-Sljukic
authors.affiliation: Center for Cardiovascular Research, Banner Sun Health Research Institute, Sun City, Arizona, USA mohamed.gaballa@bannerhealth.com.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Gaballa
mesh_terms: D000107:Acetylation; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D046509:Tissue Culture Techniques; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D001549:Benzamides; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D015850:Interleukin-6; D011743:Pyrimidines; D003094:Collagen; C523184:mocetinostat; D019009:Proto-Oncogene Proteins c-kit
keywords: Congestive heart failure; Epigenetic process; Myocardial infarct; Stem cell transplantation