STAT3 mediates cardioprotection against ischemia/reperfusion injury through metallothionein induction in the heart.
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.
Oshima
Yuichi
Y
Department of Molecular Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan.
Fujio
Yasushi
Y
Nakanishi
Tsuyoshi
T
Itoh
Norio
N
Yamamoto
Yasuhiro
Y
Negoro
Shinji
S
Tanaka
Keiichi
K
Kishimoto
Tadamitsu
T
Kawase
Ichiro
I
Azuma
Junichi
J
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
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