title: Selective inhibition of class I but not class IIb histone deacetylases exerts cardiac protection from ischemia reperfusion.
abstract: While inhibition of class I/IIb histone deacetylases (HDACs) protects the mammalian heart from ischemia reperfusion (IR) injury, class selective effects remain unexamined. We hypothesized that selective inhibition of class I HDACs would preserve left ventricular contractile function following IR in isolated hearts. Male Sprague Dawley rats (n=6 per group) were injected with vehicle (dimethylsulfoxide, 0.63mg/kg), the class I/IIb HDAC inhibitor trichostatin A (1mg/kg), the class I HDAC inhibitor entinostat (MS-275, 10mg/kg), or the HDAC6 (class IIb) inhibitor tubastatin A (10mg/kg). After 24h, hearts were isolated and perfused in Langendorff mode for 30min (Sham) or subjected to 30min global ischemia and 120min global reperfusion (IR). A saline filled balloon attached to a pressure transducer was placed in the LV to monitor contractile function. After perfusion, LV tissue was collected for measurements of antioxidant protein levels and infarct area. At the conclusion of IR, MS-275 pretreatment was associated with significant preservation of developed pressure, rate of pressure generation, rate of pressure relaxation and rate pressure product, as compared to vehicle treated hearts. There was significant reduction of infarct area with MS-275 pretreatment. Contractile function was not significantly restored in hearts treated with trichostatin A or tubastatin A. Mitochondrial superoxide dismutase (SOD2) and catalase protein and mRNA in hearts from animals pretreated with MS-275 were increased following IR, as compared to Sham. This was associated with a dramatic enrichment of nuclear FOXO3a transcription factor, which mediates the expression of SOD2 and catalase. Tubastatin A treatment was associated with significantly decreased catalase levels after IR. Class I HDAC inhibition elicits protection of contractile function following IR, which is associated with increased expression of endogenous antioxidant enzymes. Class I/IIb HDAC inhibition with trichostatin A or selective inhibition of HDAC6 with tubastatin A was not protective. This study highlights the need for the development of new strategies that target specific HDAC isoforms in cardiac ischemia reperfusion.
authors.affiliation: Gazes Cardiac Research Institute, Medical University of South Carolina, 114 Doughty St., Charleston, SC 29425, USA.
authors.forename: Sverre E
authors.initials: SE
authors.lastname: Aune
authors.affiliation: Gazes Cardiac Research Institute, Medical University of South Carolina, 114 Doughty St., Charleston, SC 29425, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Herr
authors.affiliation: Gazes Cardiac Research Institute, Medical University of South Carolina, 114 Doughty St., Charleston, SC 29425, USA.
authors.forename: Santhosh K
authors.initials: SK
authors.lastname: Mani
authors.affiliation: Gazes Cardiac Research Institute, Medical University of South Carolina, 114 Doughty St., Charleston, SC 29425, USA. Electronic address: menickd@musc.edu.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Menick
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D009924:Organ Culture Techniques; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D011725:Pyridines; C118739:entinostat; C553587:tubastatin A; C012589:trichostatin A; D002374:Catalase; D013482:Superoxide Dismutase; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Catalase; FOXO; Histone deacetylase; Ischemia reperfusion; Isolated heart; Superoxide dismutase