title: Anti-Fibrotic Effects of Class I HDAC Inhibitor, Mocetinostat Is Associated with IL-6/Stat3 Signaling in Ischemic Heart Failure.
abstract: BACKGROUND
  Recent studies have linked histone deacetylases (HDAC) to remodeling of the heart and cardiac fibrosis in heart failure. However, the molecular mechanisms linking chromatin remodeling events with observed anti-fibrotic effects are unknown. Here, we investigated the molecular players involved in anti-fibrotic effects of HDAC inhibition in congestive heart failure (CHF) myocardium and cardiac fibroblasts in vivo.
  
  
  RESULTS
  MI was created by coronary artery occlusion. Class I HDACs were inhibited in three-week post MI rats by intraperitoneal injection of Mocetinostat (20 mg/kg/day) for duration of three weeks. Cardiac function and heart tissue were analyzed at six week post-MI. CD90+ cardiac fibroblasts were isolated from ventricles through enzymatic digestion of heart. In vivo treatment of CHF animals with Mocetinostat reduced CHF-dependent up-regulation of HDAC1 and HDAC2 in CHF myocardium, improved cardiac function and decreased scar size and total collagen amount. Moreover, expression of pro-fibrotic markers, collagen-1, fibronectin and Connective Tissue Growth Factor (CTGF) were reduced in the left ventricle (LV) of Mocetinostat-treated CHF hearts. Cardiac fibroblasts isolated from Mocetinostat-treated CHF ventricles showed a decrease in expression of collagen I and III, fibronectin and Timp1. In addition, Mocetinostat attenuated CHF-induced elevation of IL-6 levels in CHF myocardium and cardiac fibroblasts. In parallel, levels of pSTAT3 were reduced via Mocetinostat in CHF myocardium.
  
  
  CONCLUSIONS
  Anti-fibrotic effects of Mocetinostat in CHF are associated with the IL-6/STAT3 signaling pathway. In addition, our study demonstrates in vivo regulation of cardiac fibroblasts via HDAC inhibition.
authors.affiliation: Cardiovascular Research Laboratory, Banner Sun Health Research Institute, Sun City, AZ 85351, USA. feyzaguvener@gmail.com.
authors.forename: Hikmet
authors.initials: H
authors.lastname: Nural-Guvener
authors.affiliation: Cardiovascular Research Laboratory, Banner Sun Health Research Institute, Sun City, AZ 85351, USA. hbssmode@yahoo.com.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Zakharova
authors.affiliation: Cardiovascular Research Laboratory, Banner Sun Health Research Institute, Sun City, AZ 85351, USA. lorraine.feehery@bannerhealth.com.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Feehery
authors.affiliation: Cardiovascular Research Laboratory, Banner Sun Health Research Institute, Sun City, AZ 85351, USA. zana.sljukic@gmail.com.
authors.forename: Snjezana
authors.initials: S
authors.lastname: Sljukic
authors.affiliation: Cardiovascular Research Laboratory, Banner Sun Health Research Institute, Sun City, AZ 85351, USA. gaballalab@gmail.com.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Gaballa
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002921:Cicatrix; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000150:complications*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D001549:Benzamides; D005353:Fibronectins; D056572:Histone Deacetylase Inhibitors; D015850:Interleukin-6; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D055513:Connective Tissue Growth Factor; D003094:Collagen; C523184:mocetinostat; D006655:Histone Deacetylases
keywords: HDAC; Mocetinostat; cardiac fibrosis; congestive heart failure; myocardial infarction