Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt
Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt
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DOI：
10.1016/j.yjmcc.2003.09.012
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发表时间：
2003-12-01
影响因子：
5
通讯作者：
Sawyer, DB
中科院分区：
文献类型：
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作者：
Fukazawa, R;Miller, TA;Sawyer, DB
我们发现神经调节蛋白-1 β（NRG-1 β）在心脏微血管内皮中表达，并通过激活erbB 2和erbB 4受体酪氨酸激酶促进培养心肌细胞的生长和存活。在这项研究中，我们研究了NRG-1/erbB信号在保护心肌细胞免受蒽环类药物诱导的细胞凋亡中的作用，以确定erbB受体亚型和细胞保护信号之间的耦合。用NRG-1 β处理新生大鼠心室肌细胞可抑制柔红霉素诱导的细胞凋亡，如末端脱氧核苷酸转移酶介导的dUTP缺口末端标记染色的DNA片段以及流式细胞术定量凋亡的心肌细胞所示。柔红霉素诱导的心肌细胞中caspase-3的激活也同样被NRG-1 β抑制。磷酸肌醇-3-激酶（PI 3-kinase）抑制剂wortmannin阻止了NRG-1 β对柔红霉素诱导的细胞凋亡和caspase-3激活的影响。NRG-1 β处理诱导Akt/PKB的快速激活，而这种激活被渥曼青霉素抑制，而腺病毒介导的显性负性Akt的过表达阻止了NRG-1 β的保护作用。Akt被NRG-1 β激活被tyrphostin AG 1478阻止，我们发现它能抑制erbB 4被NRG-1 β激活。相反，erbB 2特异性tyrphostin AG 879对Akt的NRG-1 β激活没有影响。用erbB 2激活抗体处理心肌细胞会导致erbB 2磷酸化，并导致Erk激活，但不会激活Akt。用erbB 2抗体处理对蒽环类药物诱导的细胞凋亡没有影响。因此，NRG-1 β通过erbB 4依赖性激活PI 3-激酶/Akt通路来保护蒽环类药物诱导的细胞凋亡。(C)2003 Elsevier Ltd.保留所有权利。
We have found that neuregulin-1beta (NRG-1beta) is expressed in the cardiac microvascular endothelium, and promotes the growth and survival of cardiac myocytes in culture through the activation of erbB2 and erbB4 receptor tyrosine kinases. In this study, we examined the role of NRG-1/erbB signaling in protection of cardiac myocytes from anthracycline-induced apoptosis in vitro to determine the coupling between erbB receptor subtypes and cytoprotective signaling. Treatment of neonatal rat ventricular myocytes with NRG-1beta inhibited daunorubicin-induced apoptosis as shown by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling staining for DNA fragmentation as well as flow cytometric quantification of apoptotic myocytes. Daunorubicin-induced activation of caspase-3 in cardiomyocytes was similarly inhibited by NRG-1beta. The phosphoinositol-3-kinase (PI3-kinase) inhibitor wortmannin prevented the effects of NRG-1beta on daunorubicin-induced apoptosis and activation of caspase-3. NRG-1beta treatment induced rapid activation of Akt/PKB that was inhibited by wortmannin, and adenoviral-mediated overexpression of a dominant-negative Akt prevented the protective effect of NRG-1beta. Akt activation by NRG-1beta was prevented by the tyrphostin AG1478, which we show inhibits erbB4 activation by NRG-1beta. In contrast, the erbB2-specific tyrphostin AG879 had no effect on NRG-1beta activation of Akt. Myocyte treatment with an activating antibody to erbB2 caused phosphorylation of erbB2, and led to activation of Erk but not Akt. Treatment with the erbB2 antibody had no effect on anthracycline-induced apoptosis. Thus, NRG-1beta protects against anthracycline-induced apoptosis via erbB4-dependent activation of the PI3-kinase/Akt pathway. (C) 2003 Elsevier Ltd. All rights reserved.