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.

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.

• 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)

Chemical References

• DNA-Binding Proteins
• Reactive Oxygen Species
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Trans-Activators
• 8-epi-prostaglandin F2alpha
• Metallothionein
• Dinoprost

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)