Involvement of reactive oxygen species in cardiotrophin-1-induced proliferation of cardiomyocytes differentiated from murine embryonic stem cells
Involvement of reactive oxygen species in cardiotrophin-1-induced proliferation of cardiomyocytes differentiated from murine embryonic stem cells
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DOI：
10.1016/j.yexcr.2003.10.032
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发表时间：
2004-04-01
影响因子：
3.7
通讯作者：
Wartenberg, M
中科院分区：
文献类型：
--
作者：
Sauer, H;Neukirchen, W;Wartenberg, M
心肌营养素-1(CT-1)是一种参与心肌细胞生长和存活的细胞因子。在本研究中，我们证明了用CT-1处理从多能小鼠胚胎干细胞培养出的拟胚体显著地刺激了心肌发生，并增加了增殖标记物Ki-67的核表达。自由基清除剂维生素E可抑制Ki-67表达的增加，表明ROS在信号转导中起一定作用。心肌细胞经CT-1处理后，ES细胞来源的心肌细胞内ROS升高。ROS的产生可能是由于NADPH-氧化酶抑制剂二苯基碘氯(DPI)和LY294002预培养后ROS的产生被下调，DPI和LY294002抑制磷脂酰肌醇3-激酶(PI3-激酶)。CT-1激活核因子-kappaB(NF-kappaB)，诱导Janus激酶信号转导-2(JAK-2)、信号转导和转录激活因子-3(STAT-3)以及细胞外信号调节激酶1，2(ERK1/2)的磷酸化。JAK-2拮抗剂AG490、ERK1/2抑制剂PD98059、自由基清除剂维生素E、NADPH-氧化酶抑制剂DPI以及LY294002均可抑制STAT-3和ERK1/2的磷酸化以及NF-kappaB的激活。PD98059不能抑制Jak-2的磷酸化，表明ERK和Jak/STAT信号通路在Jak-2下游水平上相互作用。结论：CT-1通过ROS参与信号转导通路，刺激ES细胞来源的心肌细胞增殖。(C)2003 Elsevier Inc.保留所有权利。
Cardiotrophin-1 (CT-1) is a cytokine that is involved in the growth and survival of cardiac cells. In the present study, we demonstrate that treatment of embryoid bodies grown from pluripotent murine embryonic stem (ES) cells with CT-1 significantly stimulated cardiomyogenesis and increased nuclear expression of the proliferation marker Ki-67. The increase in Ki-67 expression was inhibited upon pretreatment with the free radical scavenger vitamin E, indicating a role for reactive oxygen species (ROS) in the signaling cascade. CT-1 treatment of cardiac cells raised intracellular ROS in ES cell-derived cardiomyocytes. ROS were presumably generated by an NADPH-oxidase since ROS generation was down-regulated upon preincubation with the NADPH-oxidase inhibitor diphenylen iodonium chloride (DPI) and LY294002, which inhibits phosphatidylinositol 3 kinase (PI3-kinase). CT-1 activated nuclear factor-kappaB (NF-kappaB) and induced phosphorylation of the Janus kinase signal transducer-2 (Jak-2), the signal transducer and activator of transcription-3 (STAT-3) as well as the extracellular signal-regulated kinase 1,2 (ERK1/2). STAT-3 and ERK1/2 phosphorylation as well as NF-kappaB activation were inhibited by pretreatment with the Jak-2 antagonist AG490, the ERK1/2 inhibitor PD98059, the free radical scavenger vitamin E, the NADPH-oxidase inhibitor DPI, as well as by LY294002. PD98059 failed to inhibit Jak-2 phosphorylation, indicating that the ERK and the Jak/STAT signaling cascade interact on a level downstream of Jak-2. It is concluded that CT-1 stimulates the proliferation of ES cell-derived cardiomyocytes by signaling pathways that involve ROS as signaling molecules in the signal transduction cascade. (C) 2003 Elsevier Inc. All rights reserved.