Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure.
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.
Gallo
Pasquale
P
Laboratory of Molecular Cardiology, San Raffaele Science Park Foundation, Rome, Italy.
Latronico
Michael V G
MV
Gallo
Paolo
P
Grimaldi
Serena
S
Borgia
Francesco
F
Todaro
Matilde
M
Jones
Philip
P
Gallinari
Paola
P
De Francesco
Raffaele
R
Ciliberto
Gennaro
G
Steinkühler
Christian
C
Esposito
Giovanni
G
Condorelli
Gianluigi
G
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
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C102351:apicidin; D006655:Histone Deacetylases