Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure

Pasquale Gallo, Michael V G Latronico, Paolo Gallo, Serena Grimaldi, Francesco Borgia, Matilde Todaro, Philip Jones, Paola Gallinari, Raffaele De Francesco, Gennaro Ciliberto, Christian Steinkühler, Giovanni Esposito, Gianluigi Condorelli

Research output: Contribution to journalArticle

Abstract

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 α1-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.

Original languageEnglish
Pages (from-to)416-424
Number of pages9
JournalCardiovascular Research
Volume80
Issue number3
DOIs
Publication statusPublished - Dec 2008

Keywords

  • Heart failure
  • Histone deactylase inhibitors
  • Hypertrophy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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    Gallo, P., Latronico, M. V. G., Gallo, P., Grimaldi, S., Borgia, F., Todaro, M., Jones, P., Gallinari, P., De Francesco, R., Ciliberto, G., Steinkühler, C., Esposito, G., & Condorelli, G. (2008). Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure. Cardiovascular Research, 80(3), 416-424. https://doi.org/10.1093/cvr/cvn215