title: Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure.
abstract: OBJECTIVE
  Recent studies have demonstrated the importance of chromatin remodelling via histone acetylation/deacetylation for the control of cardiac gene expression. Specific histone deacetylases (HDACs) can, in fact, play a positive or negative role in determining cardiac myocyte (CM) size. Here, we report on the effect on hypertrophy development of three inhibitors (HDACi) of class I HDACs.
  
  
  RESULTS
  The compounds were first analysed in vitro by scoring hypertrophy, expression of foetal genes, and apoptosis of neonatal rat CMs stimulated with phenylephrine, an alpha1-adrenergic agonist. This initial screening indicated that a truncated derivative of apicidin with class I HDAC specificity, denoted API-D, had the highest efficacy to toxicity ratio, and was thus selected for further analysis in vivo. Administration of this drug significantly decreased myocardial hypertrophy and foetal gene expression after 1 week of pressure overload induced by thoracic aortic constriction (TAC) in mice. After 9 weeks of TAC, when manifest heart failure is encountered, mice treated with API-D presented with significantly improved echocardiographic and haemodynamic parameters of cardiac function when compared with untreated TAC-operated mice.
  
  
  CONCLUSIONS
  The apicidin derivative, API-D, is capable of reducing hypertrophy and, consequently, the transition to heart failure in mice subjected to TAC. Treatment with this substance, therefore, holds promise as an important therapeutic option for heart failure.
authors.affiliation: Laboratory of Molecular Cardiology, San Raffaele Science Park Foundation, Rome, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Gallo
authors.forename: Michael V G
authors.initials: MV
authors.lastname: Latronico
authors.forename: Paolo
authors.initials: P
authors.lastname: Gallo
authors.forename: Serena
authors.initials: S
authors.lastname: Grimaldi
authors.forename: Francesco
authors.initials: F
authors.lastname: Borgia
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
authors.forename: Paola
authors.initials: P
authors.lastname: Gallinari
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ciliberto
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy / Q000473:pathology / Q000517:prevention & control; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C102351:apicidin; D006655:Histone Deacetylases