title: Down-regulation of the transcription factor ZAC1 upon pre- and postconditioning protects against I/R injury in the mouse myocardium.
abstract: OBJECTIVE
  Myocardial infarction leads to heart failure and death. Ischaemic preconditioning (PreC) and postconditioning (PostC) reduce infarct size in animal models and human. Zac1 was identified as the only gene related to apoptosis and jointly down-regulated upon PreC and PostC. The aim of our study was to investigate the role of Zac1 down-regulation during ischaemia-reperfusion (I/R) in vivo.
  
  
  RESULTS
  C57BL/6 mice were submitted to myocardial I/R injury, PreC, or PostC protocols. QPCR and immunochemistry showed that Zac1 expression was down-regulated both at the transcriptional and the protein levels upon PreC and PostC. Zac1(-/-) Knockout mice (n = 7) developed smaller infarcts (54%) than Zac1(+/+) littermates (n = 8) and decreased apoptosis (61.7%) in the ischaemic part of the left ventricle during I/R (Zac1(-/-), n = 6 vs. Zac1(+/+), n = 7; P = 0.0012). Mutants showed under control conditions a decrease of 53.9% in mRNA of Daxx, a pro-apoptotic protein playing a key role in I/R injuries (4.81 ± 0.77, n = 4 Zac1(-/-) mice vs. 10.44 ± 3.5, n = 7 Zac1(+/+) mice; P = 0.0121).
  
  
  CONCLUSIONS
  Our study shows for the first time that Zac1 is down-regulated both at the transcriptional and protein levels upon PreC and PostC in wild-type mice. Moreover, inactivation of Zac1 in vivo is associated with a decreased amount of Daxx transcripts and, upon I/R injury, decreased infarct size and apoptosis. Altogether, our results show that Zac1 down-regulation plays a key role during cardioprotection against I/R injury and support the concept that cardioprotection regulates a network of interacting pro-apoptotic genes including Zac1 and Daxx.
authors: Institut de Génomique Fonctionnelle, F-34000 Montpellier, France.
authors: Anne
authors: A
authors: Vincent
authors: Gérald
authors: G
authors: Gahide
authors: Catherine
authors: C
authors: Sportouch-Dukhan
authors: Aurélie
authors: A
authors: Covinhes
authors: Alicia
authors: A
authors: Franck-Miclo
authors: François
authors: F
authors: Roubille
authors: Christian
authors: C
authors: Barrère
authors: Jérôme
authors: J
authors: Adda
authors: Christelle
authors: C
authors: Dantec
authors: Christelle
authors: C
authors: Redt-Clouet
authors: Christophe
authors: C
authors: Piot
authors: Joël
authors: J
authors: Nargeot
authors: Stéphanie
authors: S
authors: Barrère-Lemaire
mesh_terms: D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004452:Echocardiography; D016147:Genes, Tumor Suppressor; D057775:Ischemic Postconditioning / Q000379:methods*; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C498423:Plagl1 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors