doi: 10.1161/hc3401.095947
(Circulation. 2001;104:979.)
© 2001 American Heart Association, Inc.
Brief Rapid Communications |
Activation of Signal Transducer and Activator of Transcription 3 Protects Cardiomyocytes from Hypoxia/Reoxygenation-Induced Oxidative Stress Through the Upregulation of Manganese Superoxide Dismutase
From the Department of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (S.N., K.K., Y.F., M.F., T.O., M.I., Y.O., Y.N., H.H., T.K., K.Y.-T.), and the Gene Expression Unit, Diabetes Research Center, Vrije Universiteit, Brussels, Belgium (M.I.D., D.L.E.).
Correspondence to Keita Kunisada, MD, PhD, Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: kunisada{at}imed3.med.osaka-u.ac.jp
Background— 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).
Methods and Results— 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.
Conclusions— 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.
Key Words: antioxidants • hypoxia • signal transduction
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