Janus kinase-2 signaling mediates apoptosis in rat cardiomyocytes
Janus kinase-2 signaling mediates apoptosis in rat cardiomyocytes
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DOI：
10.1016/j.vph.2005.08.023
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发表时间：
2005-11-01
影响因子：
4
通讯作者：
Siddiqui, MAQ
中科院分区：
文献类型：
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作者：
Mascareno, E;Beckles, DL;Siddiqui, MAQ
我们测试的假设，激活Jak 2，这是显着参与了上调的肾素-血管紧张素系统（RAS），构成了一个焦点，在中继信号触发的血管紧张素II（Ang II）和缺氧/复氧分别引起心肌细胞凋亡的易感性增强。血管紧张素II处理的成年心肌细胞在培养中表现出增加的凋亡水平，伴随着促凋亡以及抗凋亡信号通路的激活。我们观察到Jak 2激酶、Stat 1、JNK的磷酸化增加，Bax蛋白表达增加，随后caspase-1和caspase-3活性增加。这些促凋亡途径的激活被Jak 2药理学抑制剂Tyrphostin AG 490阻断。我们还观察到心脏保护途径组分，即S6核糖体蛋白和热休克蛋白27（HSP 27）的磷酸化增加。同样，氧化应激，通过缺氧/复氧处理大鼠成年心肌细胞，产生依赖于激活Jak 2的凋亡。细胞凋亡反应不仅减少氯沙坦，反激动剂的AT 1，受体，但与AG 490治疗以及。综上所述，这些观察结果提供了明确的证据，有利于Jak 2信号作为心肌细胞凋亡反应的介导者。然而，有一个伴随的诱导细胞保护信号，大概提供了一个负反馈的激动剂的有害影响。(c)2005年爱思唯尔公司All rights reserved.
We tested the hypothesis that activation Jak2, which is prominently involved in the up-regulation of the renin-angiotensin system (RAS), constitutes a focal point in relaying signals triggered by a Angiotensin II (Ang II) and hypoxia/reoxygenation separately to cause an enhanced susceptibility of cardiac myocyte to apoptotic cell death. Ang II-treated adult cardiomyocytes in culture exhibited an increased level of apoptosis that accompanied activation of pro-apoptotic as well as anti-apoptotic signaling pathways. We observed increased phosphorylation of Jak2 kinase, Stat1, JNK, with increased expression of Bax protein, followed by an increase in caspase-1 and caspase-3 activity. Activation of these proapoptotic pathways was blocked by the Jak2 pharmacological inhibitor, Tyrphostin AG490. We also observed an increase in phosphorylation of cardioprotective pathway components, namely S6 ribosomal protein, and heat shock protein 27 (HSP27). Likewise, the oxidative stress, via the hypoxia/reoxygenation treatment of rat adult cardiomyocytes, produced apoptosis that was dependent upon activation of Jak2. The apoptotic response was not only reduced by Losartan, an inverse agonist of the AT1, receptor, but by treatment with AG490 as well. Taken together, these observations provide clear evidence in favor of Jak2 signaling as mediator of the apoptotic response in cardiomyocytes. However, there was a concomitant induction of cytoprotective signaling that presumably provides a negative feed-back to the deleterious effects of the agonist. (c) 2005 Elsevier Inc. All rights reserved.