Copyright © 2004, European Society of Cardiology
STAT3 mediates cardioprotection against ischemia/reperfusion injury through metallothionein induction in the heart*
aDepartment of Molecular Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
bDepartment of Clinical Evaluation of Medicines and Therapeutics, Osaka University, 1-6 Yamadaoka, Suita City, Osaka, 565-0871, Japan
cDepartment of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita City, Osaka, 565-0871, Japan
dLaboratory of Immune Regulation, Graduate School of Frontier Bioscience, Osaka University, 1-3 Yamadaoka, Suita City, Osaka, 565-0871, Japan
* Corresponding author. Tel.: +81 6 6879 8252; fax: +81 6 6879 8253. Email address: fujio{at}phs.osaka-u.ac.jp
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.
Methods and 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.
KEYWORDS Ischemia/reperfusion; Metallothionein; STAT3
* This study was partially supported by Osaka Foundation for Promotion of Clinical Immunology (to Y.F. and to Y.O.). This work was also supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan and by Health and Labour Sciences Research Grant.
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