A histone deacetylase inhibitory prodrug - Butyroyloxymethyl diethyl phosphate - Protects the heart and cardiomyocytes against ischemia injury

G. Kessler-Icekson, E. Hochhauser, T. Sinai, A. Kremer, J. Dick, N. Tarasenko, V. Nudelman, H. Schlesinger, S. Abraham, A. Nudelman, A. Rephaeli

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Abstract

Butyroyloxymethyl diethylphosphate (AN-7) is a prodrug of butyric acid effective in reducing cardiotoxicity caused by chemotherapy. In this study, we tested whether AN-7 protects the heart and cardiomyocytes against ischemia injury. A single oral dose of AN-7 was given to mice or rats. Animals were sacrificed 1.5 or 24 h later and the hearts were subjected to ischemia and reperfusion ex-vivo (Langendorff). The mechanical performance was recorded throughout and the infarct size was measured at the end of reperfusion. Neonatal rat cardiomyocytes were subjected to 24-48 h hypoxia (1% O 2) in the absence or presence of AN-7 and mitochondria damage and cell death were assessed. Proteins were analyzed by Western immunoblotting. In the two rodents, a single dose of AN-7 given in vivo preconditioned the hearts for improved functional recovery from ischemia and reperfusion performed ex-vivo. Both 1.5 h and 24 h treatments improved the pressure-related parameters whereas the coronary flow was ameliorated in the 24 h treatment only. Infarct size was smaller in the AN-7 treated hearts. In cardiomyocytes, AN-7 diminished the hypoxia induced dissipation of mitochondria membrane potential and cell death. Compared with untreated controls, AN-7-treated hearts recovering from global ischemia and cardiomyocytes undergoing hypoxia, displayed significantly higher levels of the cytoprotective heme oxygenase-1. Our findings indicate that AN-7 imparts cardioprotection against ischemia both in vivo and in vitro and emerges as a potential treatment modality for cardiac injury.

Original languageEnglish
Pages (from-to)592-599
Number of pages8
JournalEuropean Journal of Pharmaceutical Sciences
Volume45
Issue number5
DOIs
StatePublished - 11 Apr 2012

Bibliographical note

Funding Information:
This work was supported by Grants from The Israeli Ministry of Sciences and Arts (G.K.-I., A.N. and A.R.), The Chief Scientist Office in the Israeli Ministry of Health (G.K.-I.) and The Sackler Faculty of Medicine (G.K.-I.).

Funding

This work was supported by Grants from The Israeli Ministry of Sciences and Arts (G.K.-I., A.N. and A.R.), The Chief Scientist Office in the Israeli Ministry of Health (G.K.-I.) and The Sackler Faculty of Medicine (G.K.-I.).

FundersFunder number
Israeli Ministry of Sciences and Arts
Ministry of Health, State of Israel

    Keywords

    • Butyric acid
    • Cardioprotection
    • Heme oxygenase-1
    • Histone deacetylase inhibitor
    • Ischemia/reperfusion
    • Prodrug

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