Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase
Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase
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DOI：
10.1161/hc3401.095947
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发表时间：
2001-08-28
期刊：
影响因子：
37.8
通讯作者：
Yamauchi-Takihara, K
中科院分区：
文献类型：
--
作者：
Negoro, S;Kunisada, K;Yamauchi-Takihara, K
背景-心脏特异性过度表达的小鼠。信号转导和转录激活因子3(STAT3)对阿霉素诱导的损伤具有抵抗力。STAT3信号可能参与了活性氧(ROS)的解毒作用。方法与结果：白血病抑制因子(LIF)或腺病毒介导的转染法。以新生大鼠心肌细胞为实验材料，观察了组成性激活的STAT3(CaSTAT3)对缺氧/复氧(H/R)诱导的细胞内ROS形成的影响。通过2‘，7’-二氯二乙酸酯荧光素荧光检测，LIF和caSTAT3均能显著抑制H/R诱导的ROS增加。为了确定ROS是否真的参与了H/R所致的心肌细胞损伤，检测了培养上清液中肌酸磷酸激酶的含量。LIF和caSTAT3均能显著降低缺氧/复氧诱导的肌酸磷酸激酶的释放。这些结果表明，gp130/STAT3信号通过清除ROS的产生来保护H/R所致的心肌细胞损伤。为探讨其清除ROS的机制，研究了LIF对抗氧化酶的诱导作用。LiF处理显著增加了锰超氧化物歧化酶(MnSOD)基因的表达，而对过氧化氢酶和谷胱甘肽过氧化物酶基因的表达没有影响。对腺病毒介导的显性负性STAT3基因的这种诱导表达被完全阻断。此外，caSTAT3还能增强MnSODmRNA及其酶活性。此外，MnSOD的反义寡核苷酸可明显抑制LIF和caSTAT3介导的心肌保护作用。结论：STAT3的激活对心肌细胞缺氧再灌注损伤具有保护作用，其机制主要是通过诱导MnSOD来实现的。STAT3介导的信号被认为是ROS诱导的心肌细胞损伤的治疗靶点。
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.