Differential roles of GSK-3β during myocardial ischemia and ischemia/reperfusion.
Differential roles of GSK-3β during myocardial ischemia and ischemia/reperfusion.
复制标题
DOI：
10.1161/circresaha.111.249532
复制
发表时间：
2011-08-19
影响因子：
20.1
通讯作者：
Sadoshima J
中科院分区：
文献类型：
--
作者：
Zhai P;Sciarretta S;Galeotti J;Volpe M;Sadoshima J
抑制糖原合成酶激酶 3 (GSK-3) 可在缺血/再灌注 (I/R) 期间保护心脏。然而，GSK-3 β亚型特异性抑制所提供的心脏保护作用的潜在机制仍有待阐明。我们研究了介导 GSK-3β 激活/抑制对长时间缺血和 I/R 期间心肌损伤影响的分子机制。在转基因小鼠（Tg-DnGSK-3β）或杂合GSK-3β敲除小鼠（GSK-3β+/-）中，显性失活GSK-3β对GSK-3的β异构体特异性抑制显着增加，而在组成型活性GSK-3β敲入小鼠（βKI）中GSK-3β的激活显着减少，长时间缺血后心肌缺血损伤。相反，Tg-DnGSK-3β或GSK-3β+/-中GSK-3β的抑制显着减少，而βKI中GSK-3β的激活显着增强心肌I/R损伤。抑制 GSK-3β 会刺激 mTOR 信号传导，并通过雷帕霉素敏感（mTOR 依赖性）机制抑制自噬。雷帕霉素增强自噬，同时消除 GSK-3β 抑制对长期缺血性损伤和 I/R 损伤的影响。重要的是，雷帕霉素对 GSK-3β 抑制对心肌损伤的影响通过抑制自噬而逆转。我们的结果表明，GSK-3 的 β 异构体特异性抑制会加剧缺血性损伤，但通过调节 mTOR 和自噬来防止 I/R 损伤。
Inhibition of Glycogen synthase kinase-3 (GSK-3) protects the heart during ischemia/reperfusion (I/R). However, the underlying mechanisms of cardioprotection afforded by beta isoform-specific inhibition of GSK-3 remain to be elucidated. We studied the molecular mechanism mediating the effect of GSK-3β activation/inhibition upon myocardial injury during prolonged ischemia and I/R. Beta isoform-specific inhibition of GSK-3 by dominant negative GSK-3β in transgenic mice (Tg-DnGSK-3β) or in heterozygous GSK-3β knock-out mice (GSK-3β +/−) significantly increased, whereas activation of GSK-3β in constitutively active GSK-3β knock-in mice (βKI) significantly decreased, myocardial ischemic injury after prolonged ischemia. In contrast, inhibition of GSK-3β in Tg-DnGSK-3β or GSK-3β +/− significantly reduced, while activation of GSK-3β in βKI significantly enhanced, myocardial I/R injury. Inhibition of GSK-3β stimulated mTOR signaling and inhibited autophagy through a rapamycin-sensitive (mTOR-dependent) mechanism. Rapamycin enhanced autophagy and, at the same time, abolished the effects of GSK-3β inhibition on both prolonged ischemic injury and I/R injury. Importantly, the influence of rapamycin over the effects of GSK-3β inhibition on myocardial injury was reversed by inhibition of autophagy. Our results suggest that beta isoform-specific inhibition of GSK-3 exacerbates ischemic injury but protects against I/R injury by modulating mTOR and autophagy.