Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart
Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart
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DOI：
10.1161/01.res.81.4.611
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发表时间：
1997-10-01
影响因子：
20.1
通讯作者：
Ogawa, S
中科院分区：
文献类型：
--
作者：
Pan, J;Fukuda, K;Ogawa, S
本研究旨在确定在大鼠压力超负荷诱导的在体心肌肥厚过程中，JAK/STAT(即另一个激酶/信号转导和转录激活子)通路是否被激活，并证实血管紧张素II是否参与JAK/STAT通路的激活。通过缩窄Wistar大鼠腹主动脉造成急性压力超负荷。免疫沉淀-Western印迹分析显示，压力超负荷作用5分钟后，JAK1、JAK2和TYK2被激活，STAT1、STAT2和STAT3在压力超负荷后迅速被酪氨酸磷酸化。STAT1和STAT2的磷酸化在早期达到高峰，5~15min达到高峰，而STAT3的磷酸化在60min达到峰值。主动脉缩窄后即刻，干扰素活化部位/干扰素α刺激反应元件的凝胶迁移率发生移动，而诱导SIS元件的凝胶迁移率在60min时发生移动。西拉普利(血管紧张素II转换酶抑制剂)和E4177(血管紧张素II 1型[AT(1)]受体拮抗剂)均显著抑制TYK2的磷酸化，并部分抑制JAK2的磷酸化，但均不影响JAK1。AT(1)受体与JAK2或TYK2的免疫共沉淀在5分钟时明显观察到，15分钟时达到高峰(是对照组的20倍)。这些结果表明，急性压力超负荷可激活JAK/STAT通路，血管紧张素II参与激活TYK2，并通过AT1受体部分激活JAK2。血管紧张素II依赖和非依赖途径都参与了压力超负荷大鼠心脏JAK/STAT通路的激活。
This study was designed to determine whether the JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) pathway is activated in cardiac hypertrophy induced in vivo by pressure overload in rats and to demonstrate whether angiotensin II is involved in the activation of the JAK/STAT pathway. Acute pressure overload was produced by constricting the abdominal aorta of Wistar rats. Immunoprecipitation-Western blot analysis revealed that pressure overload activated JAK1, JAK2, and Tyk2 as early as 5 minutes and that STAT1, STAT2, and STAT3 were tyrosine-phosphorylated rapidly after exposure to the pressure overload. Phosphorylation of STAT1 and STAT2 peaked in the early stage at 5 to 15 minutes, whereas that of STAT3 peaked in the late stage at 60 minutes. Gel mobility shift of the interferon gamma activation site/interferon alpha-stimulating response element was observed immediately after the aortic banding, whereas the band of sis-inducing element was shifted in the late stage at 60 minutes. Both cilazapril (angiotensin II-converting enzyme inhibitor) and E4177 (angiotensin II type 1 [AT(1)] receptor antagonist) significantly suppressed the phosphorylation of Tyk2 and partially inhibited the phosphorylation of JAK2, but neither affected JAK1. Coimmunoprecipitation of the AT(1) receptor with JAK2 or Tyk2 was clearly observed at 5 minutes and peaked at 15 minutes (20-fold the control value). These results indicate that the JAK/STAT pathway is activated by acute pressure overload in rats and that angiotensin II is involved in activating Tyk2, and partially activating JAK2, via the AT, receptor. Both angiotensin II-dependent and -independent pathways take part in activating the JAK/STAT pathway in the pressure-overloaded rat heart.