A histone deacetylase inhibitory prodrug - butyroyloxymethyl diethyl phosphate - protects the heart and cardiomyocytes against ischemia injury.

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.

• Authors: G Kessler-Icekson, E Hochhauser, T Sinai, A Kremer, J Dick, N Tarasenko, V Nudelman, H Schlesinger, S Abraham, A Nudelman, A Rephaeli
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 45 Issue 5 Pg. 592-9 (Apr 11 2012) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 22234377 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Butyrates
• Histone Deacetylase Inhibitors
• Organophosphates
• Organophosphorus Compounds
• Prodrugs
• diethoxyphosphoryloxymethyl butanoate
• diethyl phosphate
• Heme Oxygenase-1
• Histone Deacetylases

Topics

• Animals
• Butyrates (pharmacology)
• Cell Death (drug effects)
• Heart (drug effects, physiopathology)
• Heme Oxygenase-1 (metabolism)
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (metabolism)
• Hypoxia (drug therapy, metabolism, physiopathology)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Inbred C57BL
• Mitochondria (drug effects, metabolism)
• Myocardial Infarction (metabolism, physiopathology, prevention & control)
• Myocardial Reperfusion Injury (metabolism, physiopathology, prevention & control)
• Myocytes, Cardiac (drug effects)
• Organophosphates (pharmacology)
• Organophosphorus Compounds (pharmacology)
• Prodrugs (pharmacology)
• Rats
• Rats, Wistar
• Regional Blood Flow
• Reperfusion