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(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

Shinji Negoro, MD, PhD; Keita Kunisada, MD, PhD; Yasushi Fujio, MD, PhD; Masanobu Funamoto, MD, PhD; Martine I. Darville, MD, PhD; Décio L. Eizirik, MD, PhD; Tomoaki Osugi, MD; Masahiro Izumi, MD; Yuichi Oshima, MD; Yoshikazu Nakaoka, MD; Hisao Hirota, MD, PhD; Tadamitsu Kishimoto, MD, PhD; Keiko Yamauchi-Takihara, MD, PhD

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

	Abstract

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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

	Introduction

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In the heart, it has been reported that reactive oxygen species (ROS) contribute to cardiac dysfunction and myocardial damage under a variety of conditions, such as ischemia-reperfusion, congestive heart failure, and doxorubicin-induced cardiomyopathy.^1–3 Recent studies have shown that gp130-mediated signals transduced both cytoprotective and hypertrophic responses in the heart.⁴ The signal transducer and activator of transcription-3 (STAT3) is a key molecule downstream of gp130, which is activated under various stressful conditions, such as pressure-overload and myocardial infarction.⁴ Transgenic mice with cardiac-specific overexpression of the STAT3 gene are protected against doxorubicin-induced cardiomyopathy.⁵ Therefore, the activation of STAT3 might induce a protective effect against oxidative stress–induced cardiomyocyte damage by scavenging ROS.

In the present study, we explored whether the gp130/STAT3 signal has a protective function against hypoxia/reoxygenation (H/R)–induced cardiomyocyte damage.

	Methods

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Cell Culture and H/R Experiments
Primary cultures of neonatal rat cardiomyocytes were prepared from the ventricles of 1-day-old Sprague-Dawley rats (Kiwa Dobutsu Wakayama, Japan), as previously described.⁶ Hypoxia was created by incubating cells in an airtight Plexiglas chamber with <1% O₂ and 5% CO₂/95% N₂ at 37°C for 2 hours using Gas Pak Plus (BBL). By replacing the medium saturated with 95% air and 5% CO₂, the cells were exposed to normoxic atmosphere (reoxygenation). Antisense oligodeoxyribonucleotides (ODN) corresponding to the initiation sites of manganese superoxide dismutase (MnSOD) translation (22 mer: CACGCCGCCCGACACAACATTG; 1.0 µmol/L) or sense ODN at the same site (22 mer: CAATGTTGTGTCGGGCGGCGTG; 1.0 µmol/L) were added to the cultured medium 18 hours before hypoxia until 24 hours after reoxygenation.⁷

Generation of Recombinant Adenovirus and Protocol of Adenovirus Infection
The recombinant replication-defective adenovirus expressing a dominant-negative form of STAT3 and constitutively activated STAT3 (caSTAT3), which were kindly provided by Drs J.F. Bromberg and J.E. Darnell, Jr (Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY),⁸ were prepared as described previously.^6,9,10 Adenovirus vector expressing ß-galactosidase (ß-gal) was used as a control.

Analysis of Intracellular ROS Generation
The fluorescent probe, 2',7'-dichlorofluorescin diacetate (DCF-DA), was used to assess intracellular ROS formation in cultured rat cardiomyocytes, as previously described.¹¹

Northern Blot Analysis and Western Blot Analysis
Northern and Western blotting were performed as previously described.⁶ Specific cDNA probes for the detection of MnSOD, catalase, and glutathione peroxidase gene transcripts were reported previously.¹²

Measurement of MnSOD Activity
MnSOD activity was determined by the nitroblue tetrazolium method.⁷

Measurement of Creatine Phosphokinase
Creatine phosphokinase (CPK) activity in the culture medium was measured by the MERCK-1-TEST CK kit (Kantou Kagaku Co).¹³

Statistical Analysis
Statistical analysis was performed by Student’s t test and 1-way ANOVA followed by Bonferroni collection for multiple group comparisons. P<0.05 was considered significant.

	Results

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Activation of Gp130/STAT3 Protects Cardiomyocytes from H/R Injury by Scavenging ROS
To examine the effects of leukemia inhibitory factor (LIF) or caSTAT3 on the intracellular ROS formation induced by H/R, DCF-DA was used as a fluorescent probe. Both LIF treatment and caSTAT3 significantly suppressed the generation of ROS induced by H/R (Figure 1A). Furthermore, they both significantly decreased H/R-induced CPK release (Figure 1B). These results indicate that the gp130/STAT3 signal protects H/R-induced cardiomyocytes injury by scavenging ROS generation.

View larger version (33K): [in this window] [in a new window]   Figure 1. Activation of gp130/STAT3 protects cardiomyocytes from H/R injury by scavenging ROS. A, LIF-treated (preincubated with 103 units/mL LIF for 6 hours) or caSTAT3-transfected cardiomyocytes were subjected to H/R (2 hours of ischemia and 24 hours of reoxygenation), and incubated with DCF-DA (5 µmol/L) for 30 minutes. Two fields were randomly selected in each well and were examined for each condition. Representative cardiomyocytes observed by laser confocal microscopy are shown. Con indicates control. B, Cardiomyocytes were treated with LIF (preincubated with 103 units/mL of LIF for 6 hours) or transfected with ß-gal or caSTAT3. CPK activity in the culture medium was measured after H/R. Data are mean±SEM from 3 experiments. *P<0.05 vs ß-gal without H/R; #P<0.05 vs ß-gal with H/R.

The Protective Effects of STAT3 Are Involved in the Upregulation of MnSOD
To explore the mechanism of protection against ROS, the effects of LIF on the induction of 3 important myocardial antioxidant enzymes (ie, MnSOD, catalase, and glutathione peroxidase) were examined. LIF treatment resulted in a significant increase of MnSOD mRNA level from 1 hour that continued for up to 24 hours, whereas the expressions of catalase and glutathione peroxidase mRNAs were unchanged throughout the time points examined (Figure 2A). Figure 2B shows the dose-dependent effect of LIF on the induction of MnSOD mRNA expression. These effects of LIF were inhibited by dominant-negative form of STAT3 (Figure 2C). Furthermore, significant enhancement of MnSOD mRNA expression was detected with caSTAT3, and this was accompanied by an increase in its enzyme activity. Thus, STAT3 is considered essential for LIF-induced MnSOD expression.

View larger version (46K): [in this window] [in a new window]   Figure 2. LIF and caSTAT3 protect from cardiomyocyte injury after H/R through the induction of MnSOD. A, Cardiomyocytes were treated with LIF (103 U/mL) and harvested at the indicated time points. MnSOD, catalase (Cat), and glutathione peroxidase (GPX) mRNA expressions were examined by Northern blot analysis. 18S indicates 18S ribosomal RNA. The results are representative of 3 similar experiments. B, Cardiomyocytes were stimulated with various concentrations of LIF for 3 hours. MnSOD mRNA expression was examined by Northern blot analysis. The results are representative of 3 similar experiments. C, Cardiomyocytes were transfected with adenovirus vectors expressing a dominant-negative form of STAT3 (dnSTAT3), caSTAT3, or ß-gal and stimulated with LIF (103 U/mL) for 3 hours. MnSOD mRNA expression was examined by Northern blot analysis. After cardiomyocytes were stimulated with LIF (103 U/mL) for 6 hours, MnSOD enzyme activity was determined as described in Methods. Data are presented as mean±SEM from 3 samples. *P<0.05 vs ß-gal without LIF stimulation; #P<0.05 vs ß-gal with LIF treatment. D, Sense or antisense ODN (1.0 µmol/L) were applied to LIF-treated (preincubated with 103 U/mL LIF for 6 hours) or ß-gal– or caSTAT3-transfected cardiomyocytes for18 hours before H/R. CPK activity in the culture medium was measured after H/R. Data are mean±SEM from 3 experiments. *P<0.05 vs LIF with sense ODN; #P<0.05 vs caSTAT3 with sense ODN.

To evaluate whether the increase in MnSOD activity is indeed directly related to the protective effect of STAT3, antisense ODN against the MnSOD gene were used. Antisense ODN completely cancelled both LIF and caSTAT3-induced MnSOD activities, and sense ODN did not affect our experiments (data not shown). As shown in Figure 2D, these beneficial effects of LIF and caSTAT3 on CPK release were significantly decreased in the presence of antisense ODN. Thus, the protective effects of STAT3 against H/R are mainly related to the induction of MnSOD activity.

	Discussion

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The major new finding in the present study is that STAT3 activation protects cardiomyocytes against ROS caused by H/R through the upregulation of the MnSOD gene and its enzyme activity.

Endotoxin and cytokines such as tumor necrosis factor-, interleukin-1ß, and interluekin-6 are known to induce MnSOD, and several studies have confirmed the cardioprotective role of MnSOD.^14–16 In view of the transcriptional regulation, 3 interferon- activation site motifs (TTCCTCTAA, TTCCTCAA, and TTACATCAA) that are bound with activated STAT3 were identified in the region spanning from –2505 to –1104 in the MnSOD promoter region.^17,18 This suggests that LIF induce MnSOD mRNA expression mainly via the STAT3 binding cis-element in cardiac myocytes. It remains to be identified which motifs of the 3 discussed above are the most important for the induction of the MnSOD gene.

To clarify the role of MnSOD in H/R, we used an antisense strategy to suppress MnSOD induction.⁷ The responses to the pretreatment with antisense ODN in caSTAT3- or LIF-treated cells were different. The protective effects observed in caSTAT3 transduction were nearly completely abolished with antisense ODN, whereas the protective effects by LIF were not completely abolished with antisense ODN. These results suggest that induction of MnSOD by caSTAT3 is essential for caSTAT3-induced protection in H/R. The genes related to cardiac protection, such as the atrial natriuretic factor and vascular endothelial growth factor genes, increased in the hearts with cardiac-specific overexpression of STAT3; however, these genes have little effect on this condition.⁵ However, LIF stimulation induces other anti-apoptotic molecules, such as Bcl-xL and Bcl-2, and also activates phosphatidylinositol 3 kinase-Akt and mitogen-activated protein kinase pathways, which would be involved in a protective effect against ROS.^4,19,20 Therefore, LIF presents more protective effects than STAT3 by inducing other protective factors besides MnSOD.

We propose that the activation of STAT3 could be a therapeutic strategy for cardiac protection against ROS-mediated cytotoxicity in several pathological conditions.

	Acknowledgments

 
This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan; grants from the Ministry of Health and Welfare of Japan; and the Takeda Science Foundation. We thank Jurei Hironaka for her secretarial assistance.

Received April 30, 2001; revision received July 9, 2001; accepted July 10, 2001.

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