title: STAT3 mediates cardioprotection against ischemia/reperfusion injury through metallothionein induction in the heart.
abstract: OBJECTIVE
  Activation of signal transducer and activator of transcription 3 (STAT3) was reported to be correlated with myocardial protection against ischemia/reperfusion (I/R) injury in ischemic preconditioning. Here, we tested the causality between STAT3 activity and cardioprotection. We also addressed the molecular mechanism for its cardioprotection.
  
  
  RESULTS
  Cardiac-specific transgenic mice expressing constitutively active STAT3 (TG) were generated and exposed to I/R injury. TG hearts exhibited infarcts that reduced by 60.3% in size, compared with nontransgenic littermates (NTG). By measuring dichlorofluorescein (DCF) and 8-isoprostane, reactive-oxygen-species (ROS)-induced metabolites, it was revealed that ROS were generated to lesser extent in TG hearts than in NTG in response to I/R stress. In parallel, ROS scavengers, metallothionein1 (MT1), and metallothionein2 (MT2) were markedly up-regulated in TG hearts. Finally, homozygous deletion of the MT1 and MT2 genes abrogated cardioprotective effect of STAT3 against I/R injury with the cancellation of its ROS-scavenging effects.
  
  
  CONCLUSIONS
  Activation of STAT3 protects myocardium from I/R injury in vivo. STAT3 mediates cardioprotection at least partially through MT1 and 2. STAT3 is a potential therapeutic target for I/R injury.
authors.affiliation: Department of Molecular Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oshima
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Norio
authors.initials: N
authors.lastname: Itoh
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Negoro
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
authors.forename: Junichi
authors.initials: J
authors.lastname: Azuma
mesh_terms: D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C075750:8-epi-prostaglandin F2alpha; D008668:Metallothionein; D015237:Dinoprost