Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse
Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse
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DOI：
10.1161/circresaha.107.169953
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发表时间：
2008-08-01
影响因子：
20.1
通讯作者：
Marber, Michael S.
中科院分区：
文献类型：
--
作者：
Nishino, Yasuhiro;Webb, Ian G.;Marber, Michael S.
糖原合成酶激酶-3 β（GSK-3 β）的失活被认为是预处理和其他干预措施启动的整合保护途径的事件。GSK-3的失活被认为降低了线粒体通透性转换孔开放的可能性。本研究的目的是使用缺乏GSK-3 β（Ser 9）和高度同源GSK-3 β（Ser 21）内的关键N-末端丝氨酸的靶向小鼠系验证GSK-3的作用，当磷酸化时导致激酶失活。10个循环的5秒再灌注/5秒缺血的后处理和6个循环的4分钟缺血/6分钟再灌注的预处理，类似地减少了响应于30分钟全脑缺血和120分钟再灌注的离体灌注小鼠心脏的梗塞。预处理引起明显的GSK-3磷酸化失活。然而，预处理和后处理仍然保护纯合子GSK-3双敲入小鼠的心脏。此外，直接药理学抑制GSK-3的催化活性与结构不同的抑制剂缺血前或缺血后未能重演空调保护。尽管如此，环孢菌素A，一种直接的线粒体通透性转换孔抑制剂，减少了野生型和纯合子GSK-3双敲入小鼠的心脏梗死。此外，在GSK-3双敲入小鼠的成年心肌细胞中，胰岛素暴露在延迟线粒体通透性转换孔开放方面仍然与环孢菌素A一样有效。我们的研究结果，其中包括一种新的遗传方法，表明GSK-3的抑制是不太可能的心脏保护信号在预处理或后处理在小鼠的关键决定因素。
The inactivation of glycogen synthase kinase-3 beta (GSK-3 beta) is proposed as the event integrating protective pathways initiated by preconditioning and other interventions. The inactivation of GSK-3 is thought to decrease the probability of opening of the mitochondrial permeability transition pore. The aim of this study was to verify the role of GSK-3 using a targeted mouse line lacking the critical N-terminal serine within GSK-3 beta (Ser9) and the highly homologous GSK-3 beta (Ser21), which when phosphorylated results in kinase inactivation. Postconditioning with 10 cycles of 5 seconds of reperfusion/5 seconds of ischemia and preconditioning with 6 cycles of 4 minutes of ischemia/6 minutes of reperfusion, similarly reduced infarction of the isolated perfused mouse heart in response to 30 minutes of global ischemia and 120 minutes of reperfusion. Preconditioning caused noticeable inactivating phosphorylation of GSK-3. However, both preconditioning and postconditioning still protected hearts of homozygous GSK-3 double knockin mice. Moreover, direct pharmacological inhibition of GSK-3 catalytic activity with structurally diverse inhibitors before or after ischemia failed to recapitulate conditioning protection. Nonetheless, cyclosporin A, a direct mitochondrial permeability transition pore inhibitor, reduced infarction in hearts from both wild-type and homozygous GSK-3 double knockin mice. Furthermore, in adult cardiac myocytes from GSK-3 double knockin mice, insulin exposure was still as effective as cyclosporin A in delaying mitochondrial permeability transition pore opening. Our results, which include a novel genetic approach, suggest that the inhibition of GSK-3 is unlikely to be the key determinant of cardioprotective signaling in either preconditioning or postconditioning in the mouse.