Cardiovascular Research Advance Access first published online on August 12, 2008
This version [Corrected Proof] published online on August 27, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn215
Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure
1 Laboratory of Molecular Cardiology, San Raffaele Science Park Foundation, Rome, Italy
2 Istituto di Ricerche di Biologia Molecolare P. Angeletti, IRBM-Merck Research Laboratories Rome, Pomezia, Italy
3 Laboratory of Genetic and Molecular Cardiology, Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy
4 Campus Bio-Medico di Roma, Rome, Italy
5 Division of Cardiology, Federico II University, Naples, Italy
6 Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy
7 Division of Cardiology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, BSB 5022, La Jolla, CA 92093-0613, USA
* Corresponding author. Tel: +1 858 822 5010; fax: + 1 858 822 3027. E-mail address: gcondorelli{at}ucsd.edu
Aims: 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.
Methods and 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 
1-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.
Conclusion: 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.
KEYWORDS Hypertrophy; Heart failure; Histone deactylase inhibitors
Time for primary review: 29 days
These authors contributed equally to the work.
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