title: 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.affiliation: Felsenstein Medical Research Center, Tel-Aviv University, Israel. icekson@post.tau.ac.il
authors.forename: G
authors.initials: G
authors.lastname: Kessler-Icekson
authors.forename: E
authors.initials: E
authors.lastname: Hochhauser
authors.forename: T
authors.initials: T
authors.lastname: Sinai
authors.forename: A
authors.initials: A
authors.lastname: Kremer
authors.forename: J
authors.initials: J
authors.lastname: Dick
authors.forename: N
authors.initials: N
authors.lastname: Tarasenko
authors.forename: V
authors.initials: V
authors.lastname: Nudelman
authors.forename: H
authors.initials: H
authors.lastname: Schlesinger
authors.forename: S
authors.initials: S
authors.lastname: Abraham
authors.forename: A
authors.initials: A
authors.lastname: Nudelman
authors.forename: A
authors.initials: A
authors.lastname: Rephaeli
mesh_terms: D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010755:Organophosphates / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow; D015424:Reperfusion
chemical_list: D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D010755:Organophosphates; D009943:Organophosphorus Compounds; D011355:Prodrugs; C502471:diethoxyphosphoryloxymethyl butanoate; C034789:diethyl phosphate; D051547:Heme Oxygenase-1; D006655:Histone Deacetylases