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. 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.
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Authors | Yuichi Oshima, Yasushi Fujio, Tsuyoshi Nakanishi, Norio Itoh, Yasuhiro Yamamoto, Shinji Negoro, Keiichi Tanaka, Tadamitsu Kishimoto, Ichiro Kawase, Junichi Azuma |
Journal | Cardiovascular research
(Cardiovasc Res)
Vol. 65
Issue 2
Pg. 428-35
(Feb 01 2005)
ISSN: 0008-6363 [Print] England |
PMID | 15639482
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- DNA-Binding Proteins
- Reactive Oxygen Species
- STAT3 Transcription Factor
- Stat3 protein, mouse
- Trans-Activators
- 8-epi-prostaglandin F2alpha
- Metallothionein
- Dinoprost
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Topics |
- Animals
- Blotting, Northern
(methods)
- Blotting, Western
(methods)
- DNA-Binding Proteins
(genetics, metabolism)
- Dinoprost
(analogs & derivatives, metabolism)
- Ischemic Preconditioning, Myocardial
- Male
- Metallothionein
(metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Models, Animal
- Myocardial Reperfusion Injury
(metabolism, prevention & control)
- Myocardium
(metabolism)
- Reactive Oxygen Species
(analysis, metabolism)
- STAT3 Transcription Factor
- Trans-Activators
(genetics, metabolism)
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