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

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

Risultato della ricerca: Article

88 Citazioni (Scopus)

Abstract

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.The compounds were first analysed in vitro by scoring hypertrophy, expression of foetal genes, and apoptosis of neonatal rat CMs stimulated with phenylephrine, an alpha 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.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.
Lingua originaleEnglish
pagine (da-a)416-424
Numero di pagine9
RivistaCardiovascular Research
Volume80
Stato di pubblicazionePublished - 2008

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Histone Deacetylases
Cardiomegaly
Constriction
Hypertrophy
Thorax
Heart Failure
Gene Expression
Adrenergic alpha-1 Receptor Agonists
Chromatin Assembly and Disassembly
Phenylephrine
Acetylation
Cardiac Myocytes
Histones
Hemodynamics
Apoptosis
Pressure
apicidin
Pharmaceutical Preparations
Therapeutics

All Science Journal Classification (ASJC) codes

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

Cita questo

Todaro, M., Gallo, P., Latronico, M. V. G., Jones, P., Ciliberto, G., Esposito, G., ... Grimaldi, S. (2008). Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure. Cardiovascular Research, 80, 416-424.

Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure. / Todaro, Matilde; Gallo, Pasquale; Latronico, Michael V.G.; Jones, Philip; Ciliberto, Gennaro; Esposito, Giovanni; Gallo, Paolo; Borgia, Francesco; Condorelli, Gianluigi; Steinkühler, Christian; De Francesco, Raffaele; Gallinari, Paola; Grimaldi, Serena.

In: Cardiovascular Research, Vol. 80, 2008, pag. 416-424.

Risultato della ricerca: Article

Todaro, M, Gallo, P, Latronico, MVG, Jones, P, Ciliberto, G, Esposito, G, Gallo, P, Borgia, F, Condorelli, G, Steinkühler, C, De Francesco, R, Gallinari, P & Grimaldi, S 2008, 'Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure.', Cardiovascular Research, vol. 80, pagg. 416-424.
Todaro, Matilde ; Gallo, Pasquale ; Latronico, Michael V.G. ; Jones, Philip ; Ciliberto, Gennaro ; Esposito, Giovanni ; Gallo, Paolo ; Borgia, Francesco ; Condorelli, Gianluigi ; Steinkühler, Christian ; De Francesco, Raffaele ; Gallinari, Paola ; Grimaldi, Serena. / Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure. In: Cardiovascular Research. 2008 ; Vol. 80. pagg. 416-424.
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abstract = "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.The compounds were first analysed in vitro by scoring hypertrophy, expression of foetal genes, and apoptosis of neonatal rat CMs stimulated with phenylephrine, an alpha 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.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.",
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AU - Todaro, Matilde

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AU - Latronico, Michael V.G.

AU - Jones, Philip

AU - Ciliberto, Gennaro

AU - Esposito, Giovanni

AU - Gallo, Paolo

AU - Borgia, Francesco

AU - Condorelli, Gianluigi

AU - Steinkühler, Christian

AU - De Francesco, Raffaele

AU - Gallinari, Paola

AU - Grimaldi, Serena

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N2 - 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.The compounds were first analysed in vitro by scoring hypertrophy, expression of foetal genes, and apoptosis of neonatal rat CMs stimulated with phenylephrine, an alpha 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.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.

AB - 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.The compounds were first analysed in vitro by scoring hypertrophy, expression of foetal genes, and apoptosis of neonatal rat CMs stimulated with phenylephrine, an alpha 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.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.

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