Role of STAT3 in ischemic preconditioning
Role of STAT3 in ischemic preconditioning
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DOI：
10.1006/jmcc.2001.1456
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发表时间：
2001-11-01
影响因子：
5
通讯作者：
Das, DK
中科院分区：
文献类型：
--
作者：
Hattori, R;Maulik, N;Das, DK
我们最近证明，短时间缺血和再灌注周期性发作诱导的缺血预处理（IPC）增强了涉及蛋白质酪氨酸激酶和MAP激酶的信号传导级联反应。在心肌缺血和再灌注过程中，Janus激酶（JAK）和包括STAT 3、STAT 5A和STAT 6在内的几种信号转导和转录激活因子（STAT）被迅速激活。本研究旨在探讨JAK/STAT信号通路是否在IPC的经典早期阶段发挥作用。在不存在或存在JAK激酶抑制剂tyrphostin AG 490（5 μ M）的情况下，用KHB缓冲液灌注分离的工作大鼠心脏15分钟，随后进行IPC，30分钟全脑缺血和2小时再灌注。结果表明，IPC心脏中JAK 2和STAT 3的广泛磷酸化几乎被JAK 2的抑制剂AG 490完全消除。IPC表现出心脏保护作用，表现为改善缺血后收缩恢复，减少心肌梗死面积和减少凋亡心肌细胞数量。AG 490通过将IPC介导的存活信号改变为死亡信号来阻断IPC介导的心脏保护作用。因此，IPC诱导的抗凋亡基因bcl-2的上调和促凋亡基因bax的下调分别在AG 490处理的心脏中减少和增加。结果表明，IPC的早期阶段通过激活STAT 3来增强JAK/STAT信号传导，STAT 3将存活信号传递到心肌。(C)北京：科学出版社.
We recently demostrated that ischemic preconditioning (IPC) induced by cyclic episodes of short durations of ischemia and reperfusion potentiates a signal transduction cascade involving protein tyrosine kinases and MAP kinases. A rapid activation of janus kinase (JAK) and several signal transducers and activators of the transcription (STATs) including STAT3, STAT5A and STAT6 has been shown to occur during myocardial ischemia and reperfusion. This study sought to examine if JAK/STAT signaling pathway play any role in classical early phase of IPC. Isolated working rat hearts were perfused for 15 min with KHB buffer in the absence or presence of a JAK kinase inhibitor tyrphostin AG490 (5 muM) followed by IPC, 30 min global ischemia and 2 h of reperfusion. The results demonstrated extensive phosphorylation of JAK2 and STAT3 in the IPC hearts which was almost completely abolished by an inhibitor of JAK2, AG490. IPC displayed cardioprotection as evidenced by improved post-ischemic contractile recovery, decreased myocardial infarct size and reduced number of apoptotic cardiomyocytes. AG490 blocked IPC-mediated cardioprotection by altering the IPC-mediated survival signal into death signal. Thus, IPC-induced upregulation of antiapoptotic gene bcl-2 and downregulation of pro-apoptotic gene bax are decreased and increased, respectively, in the AG490 treated hearts. The results suggest that early phase of IPC potentiates JAK/STAT signaling by activating STAT3 which transmits a survival signal to the myocardium. (C) 2001 Academic Press.