Article

Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase.

Department of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Circulation (impact factor: 14.74). 09/2001; 104(9):979-81. pp.979-81
Source: PubMed

ABSTRACT Mice with cardiac-specific overexpression of signal transducer and activator of transcription 3 (STAT3) are resistant to doxorubicin-induced damage. The STAT3 signal may be involved in the detoxification of reactive oxygen species (ROS).
The effects of leukemia inhibitory factor (LIF) or adenovirus-mediated transfection of constitutively activated STAT3 (caSTAT3) on the intracellular ROS formation induced by hypoxia/reoxygenation (H/R) were examined using rat neonatal cardiomyocytes. Either LIF treatment or caSTAT3 significantly suppressed the increase of H/R-induced ROS evaluated by 2',7'-dichlorofluorescin diacetate fluorescence. To assess whether ROS are really involved in H/R-induced cardiomyocyte injury, the amount of creatine phosphokinase in cultured medium was examined. Both LIF treatment and caSTAT3 significantly decreased H/R-induced creatine phosphokinase release. These results indicate that the gp130/STAT3 signal protects H/R-induced cardiomyocyte injury by scavenging ROS generation. To investigate the mechanism of scavenging ROS, the effects of LIF on the induction of antioxidant enzymes were examined. LIF treatment significantly increased the expression of manganese superoxide dismutase (MnSOD) mRNA, whereas the expression of the catalase and glutathione peroxidase genes were unaffected. This induction of MnSOD mRNA expression was completely blocked by adenovirus-mediated transfection of dominant-negative STAT3. Moreover, caSTAT3 augmented MnSOD mRNA and its enzyme activity. In addition, the antisense oligodeoxyribonucleotide to MnSOD significantly inhibited both LIF and caSTAT3-mediated protective effects.
The activation of STAT3 induces a protective effect on H/R-induced cardiomyocyte damage, mainly by inducting MnSOD. The STAT3-mediated signal is proposed as a therapeutical target of ROS-induced cardiomyocyte injury.

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Keywords

adenovirus-mediated transfection
 
caSTAT3
 
caSTAT3 augmented MnSOD mRNA
 
caSTAT3-mediated protective effects
 
constitutively activated STAT3
 
cultured medium
 
dominant-negative STAT3
 
H/R-induced cardiomyocyte damage
 
H/R-induced cardiomyocyte injury
 
H/R-induced creatine phosphokinase release
 
H/R-induced ROS
 
intracellular ROS formation induced
 
leukemia inhibitory factor
 
LIF treatment
 
manganese superoxide dismutase
 
ROS-induced cardiomyocyte injury
 
scavenging ROS
 
scavenging ROS generation
 
STAT3-mediated signal
 
transcription 3