Reactive oxygen species regulate heat-shock protein 70 via the JAK/STAT pathway
Reactive oxygen species regulate heat-shock protein 70 via the JAK/STAT pathway
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DOI：
10.1161/01.atv.21.3.321
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发表时间：
2001-03-01
影响因子：
8.7
通讯作者：
Runge, MS
中科院分区：
文献类型：
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作者：
Madamanchi, NR;Li, SZ;Runge, MS
过氧化氢 (H2O2) 等活性氧 (ROS) 会激活与心血管疾病发病机制有关的细胞内信号转导途径。 H2O2 是大鼠血管平滑肌细胞 (VSMC) 的有丝分裂原，蛋白质酪氨酸磷酸化是 VSMC 有丝分裂发生的关键事件。因此，我们研究了 H2O2 的促有丝分裂作用，例如刺激细胞外信号调节激酶 (ERK)2，是否是通过激活细胞质 Janus 酪氨酸激酶 (JAK) 介导的。 JAK2 在 H2O2 处理的 VSMC 中迅速激活，信号转导子和转录激活子 (STAT) STAT1 和 STAT3 被酪氨酸磷酸化，并以 JAK2 依赖性方式转位至细胞核。用 AG-490 抑制 JAK2 活性可部分抑制 H2O2 诱导的 ERK2 活性，表明 JAK2 位于 Ras/Raf/丝裂原激活蛋白激酶 -ERK/ERK 有丝分裂途径的上游。由于热休克蛋白 (HSP) 可以保护细胞免受 ROS 的侵害，因此我们研究了 H2O2 对 HSP 表达的影响。 H2O2 以时间依赖性方式刺激 HSP70 表达，AG-490 消除 H2O2 诱导的 HSP70 表达。 H2O2 通过增强 STAT 与启动子中同源结合位点的结合来激活 HSP70 启动子。通过激活 JAK/STAT 通路对 HSP70 等伴侣分子的调节表明，除了其生长促进作用外，该通路还可能有助于 VSMC 适应氧化应激。
Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) activate intracellular signal transduction pathways implicated in the pathogenesis of cardiovascular disease. H2O2 is a mitogen for rat vascular smooth muscle cells (VSMCs), and protein tyrosine phosphorylation is a critical event in VSMC mitogenesis. Therefore, we investigated whether the mitogenic effects of H2O2, such as stimulation of extracellular signal-regulated kinase (ERK)2, are mediated via activation of cytoplasmic Janus tyrosine kinases (JAKs). JAK2 was activated rapidly in VSMCs treated with H2O2, and signal transducers and activators of transcription (STAT) STAT1 and STAT3 were tyrosine-phosphorylated and translocated to the nucleus in a JAK2-dependent manner. Inhibition of JAK2 activity with AG-490 partially inhibited H2O2-induced ERK2 activity, suggesting that JAK2 is upstream of the Ras/Raf/mitogen-activated protein kinase-ERK/ERK mitogenic pathway. Because heat-shock proteins (HSPs) can protect cells from ROS, we investigated the effect of H2O2 on HSP expression. H2O2 stimulated HSP70 expression in a time-dependent manner, and AG-490 abolished H2O2-induced HSP70 expression. H2O2 activated the HSP70 promoter via enhanced binding of STATs to cognate binding sites in the promoter. Regulation of chaperones such as HSP70 via activation of the JAK/STAT pathway suggests that in addition to its growth-promoting effects, this pathway may help VSMCs adapt to oxidative stress.