title: Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy.
abstract: BACKGROUND
  Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor approved for cancer treatment by the US Food and Drug Administration, will blunt reperfusion injury.
  
  
  RESULTS
  Twenty-one rabbits were randomly assigned to 3 groups: (1) vehicle control, (2) SAHA pretreatment (1 day before and at surgery), and (3) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (30 minutes coronary ligation, 24 hours reperfusion). In addition, cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated ischemia/reperfusion to probe mechanism. SAHA reduced infarct size and partially rescued systolic function when administered either before surgery (pretreatment) or solely at the time of reperfusion. SAHA plasma concentrations were similar to those achieved in patients with cancer. In the infarct border zone, SAHA increased autophagic flux, assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to simulated ischemia/reperfusion, SAHA pretreatment reduced cell death by 40%. This reduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA's cardioprotective effects.
  
  
  CONCLUSIONS
  The US Food and Drug Administration-approved anticancer histone deacetylase inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during ischemia/reperfusion occur, at least in part, through the induction of autophagic flux.
authors.affiliation: Departments of Internal Medicine (Cardiology) (M.X., Y.K., W.Y., H.M., P.K.B., Z.P., Z.V.W., C.M., X.L., G.C., N.J., J.J.W., S.L., T.G.G., A.T.T., J.A.H.), Cardiovascular and Thoracic Surgery (M.E.J.), Advanced Center for Chronic Diseases (ACCDiS) & Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile (S.L.); and the Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas (J.A.H.).
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.forename: Yongli
authors.initials: Y
authors.lastname: Kong
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.forename: Herman
authors.initials: H
authors.lastname: May
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Battiprolu
authors.forename: Zully
authors.initials: Z
authors.lastname: Pedrozo
authors.forename: Zhao V
authors.initials: ZV
authors.lastname: Wang
authors.forename: Cyndi
authors.initials: C
authors.lastname: Morales
authors.forename: Xiang
authors.initials: X
authors.lastname: Luo
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Cho
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jessen
authors.forename: John J
authors.initials: JJ
authors.lastname: Warner
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Gillette
authors.forename: Aslan T
authors.initials: AT
authors.lastname: Turer
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D000077337:Vorinostat; D006655:Histone Deacetylases
keywords: autophagy; cell death; histone deacetylases; myocardial infarction; reperfusion injury