title: Myocardial expression of a dominant-negative form of Daxx decreases infarct size and attenuates apoptosis in an in vivo mouse model of ischemia/reperfusion injury.
abstract: BACKGROUND
  Apoptosis has been described extensively in acute myocardial infarction and chronic heart failure. Because Daxx (death-associated protein) appears to be essential for stress-induced cell death and acts as an antisurvival molecule, we tested the hypothesis that Daxx is involved in myocardial ischemia/reperfusion-induced cell death in vivo.
  
  
  RESULTS
  Transgenic mice overexpressing a dominant-negative form of Daxx (Daxx-DN) under the control of the beta-actin promoter and control wild-type mice underwent an ischemia/reperfusion protocol: 40 minutes of left coronary artery occlusion and 60 minutes of reperfusion. Area at risk and infarct size were measured after dual staining by triphenyltetrazolium chloride and phthalocyanine blue dye. Apoptosis was measured in the ischemic versus the nonischemic part of the left ventricle by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling staining, enzyme-linked immunosorbent assay, and Western blotting of caspase-3, caspase-8, and poly(ADP-ribose) polymerase. The mitogen-activated protein kinase status was investigated by Western blot analysis. Comparison between groups was assessed by ANOVA or Student t test (statistical significance: P<0.05). Left ventricle tissues from transgenic mice expressed Daxx-DN at the protein level. Area at risk/left ventricle values were comparable among groups. Infarct size/area at risk was 45% reduced in Daxx-DN versus wild-type mice (P<0.001). This cardioprotection was maintained for a 4-hour reperfusion. Ischemia/reperfusion-induced apoptosis was significantly decreased and ERK1/2 prosurvival pathway was activated in ischemic Daxx-DN hearts.
  
  
  CONCLUSIONS
  Our study clearly indicates that Daxx participates in myocardial ischemia/reperfusion proapoptotic signaling in vivo.
authors.affiliation: Department of Physiology CNRS UMR5203, INSERM U661, University of Montpellier I and II, 141 rue de la Cardonille, 34094 Montpellier, Cedex 5, France. stephanie.barrere@igf.cnrs.fr
authors.forename: François
authors.initials: F
authors.lastname: Roubille
authors.forename: Stéphane
authors.initials: S
authors.lastname: Combes
authors.forename: Juani
authors.initials: J
authors.lastname: Leal-Sanchez
authors.forename: Christian
authors.initials: C
authors.lastname: Barrère
authors.forename: Frédéric
authors.initials: F
authors.lastname: Cransac
authors.forename: Catherine
authors.initials: C
authors.lastname: Sportouch-Dukhan
authors.forename: Gérald
authors.initials: G
authors.lastname: Gahide
authors.forename: Isabelle
authors.initials: I
authors.lastname: Serre
authors.forename: Elodie
authors.initials: E
authors.lastname: Kupfer
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
authors.forename: Anne-Odile
authors.initials: AO
authors.lastname: Hueber
authors.forename: Joël
authors.initials: J
authors.lastname: Nargeot
authors.forename: Christophe
authors.initials: C
authors.lastname: Piot
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Barrère-Lemaire
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002908:Chronic Disease; D056970:Co-Repressor Proteins; D004195:Disease Models, Animal; D005799:Genes, Dominant; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018832:Molecular Chaperones; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C491473:Daxx protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C505409:Casp3 protein, mouse; D053148:Caspase 3; D053181:Caspase 8