Mechanical stretch activates the JAK STAT pathway in rat cardiomyocytes
Mechanical stretch activates the JAK STAT pathway in rat cardiomyocytes
复制标题
DOI：
10.1161/01.res.84.10.1127
复制
发表时间：
1999-05-28
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
本研究旨在确定机械拉伸是否激活心肌细胞中的Janus激酶（JAK）/信号转导和转录激活因子（STAT）通路，如果是，则通过何种机制激活。将新生大鼠/小鼠心肌细胞培养在延展性硅胶皿上，并拉伸20%。机械牵张诱导JAK 1、JAK 2、Tyk 2、STAT 1、STAT 3和糖蛋白130的快速磷酸化早在2分钟，并在5至15分钟达到峰值。它也引起了凝胶迁移率的SIS诱导元件，这是超移动的预孵育与抗STAT 3抗体。AT（1）阻断剂CV11974可部分抑制STAT 1的磷酸化，但对STAT 3的磷酸化无明显影响。用TAK 044（内皮素-1-A/B型受体阻断剂）预孵育不会减弱该途径。RX 435（抗糖蛋白130阻断抗体）抑制STAT 3的磷酸化，并部分抑制STAT 1的磷酸化。STAT 1和STAT 3的磷酸化被HOE 642（Na+H+交换抑制剂）和BAPTA-AM（细胞内钙螯合剂）强烈抑制，但不被钆（牵张激活离子通道抑制剂）、EGTA（细胞外Ca 2+螯合剂）或KN 62（Ca 2 +/钙调蛋白激酶II抑制剂）抑制。白屈菜红碱（蛋白激酶C抑制剂）部分抑制STAT 1和STAT 3的磷酸化。机械牵张60 ~ 120分钟后，心肌营养素-1、白细胞介素-6和白血病抑制因子的mRNA表达也增加。这些结果表明，JAK/STAT途径被机械拉伸激活，并且这种激活部分依赖于自分泌/旁分泌分泌的血管紧张素II，并且主要依赖于白细胞介素-6家族的细胞因子，但不依赖于内皮素-1。此外，一定水平的细胞内Ca 2+是必要的拉伸诱导激活这一途径，蛋白激酶C也部分参与了这一激活。
This study was designed to determine whether mechanical stretch activates the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and, if so, by what mechanism. Neonatal rat/murine cardiomyocytes were cultured on malleable silicone dishes and were stretched by 20%. Mechanical stretch induced rapid phosphorylation of JAK1, JAK2, Tyk2, STAT1, STAT3, and glycoprotein 130 as early as 2 minutes and peaked at 5 to 15 minutes. It also caused gel mobility shift of sis-inducing element, which was supershifted by preincubation with anti-STAT3 antibody. Preincubation with CV11974 (AT(1) blocker) partially inhibited the phosphorylation of STAT1, but not that of STAT3. Preincubation with TAK044 (endothelin-1-type A/B-receptor blocker) did not attenuate this pathway. RX435 (anti-glycoprotein 130 blocking antibody) inhibited the phosphorylation of STAT3 and partially inhibited that of STAT1. Phosphorylation of STAT1 and STAT3 was strongly inhibited by HOE642 (Na+H+ exchanger inhibitor) and BAPTA-AM (intracellular calcium chelator), but not by gadolinium (stretch-activated ion channel inhibitor), EGTA (extracellular Ca2+ chelator), or KN62 (Ca2+/calmodulin kinase II inhibitor). Chelerythrine (protein kinase C inhibitor) partially inhibited the phosphorylation of STAT1 and STAT3. Mechanical stretch also augmented the mRNA expression of cardiotrophin-1, interleukin-6, and leukemia inhibitory factor at 60 to 120 minutes. These results indicated that the JAK/STAT pathway was activated by mechanical stretch, and that this activation was partially dependent on autocrine/paracrine-secreted angiotensin II and was mainly dependent on the interleukin-6 family of cytokines but was independent of endothelin-1. Moreover, certain levels of intracellular Ca2+ were necessary for stretch-induced activation of this pathway, and protein kinase C was also partially involved in this activation.