Induction of protein synthesis in cardiac fibroblasts by cardiotrophin-1: integration of multiple signaling pathways
Induction of protein synthesis in cardiac fibroblasts by cardiotrophin-1: integration of multiple signaling pathways
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DOI：
10.1016/s0008-6363(03)00534-0
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发表时间：
2003-11-01
影响因子：
10.8
通讯作者：
Dixon, IMC
中科院分区：
文献类型：
--
作者：
Freed, DH;Borowiec, AM;Dixon, IMC
目的：心肌营养素-1(CT-1)是细胞因子IL-6家族的一员，在多种心血管疾病中均有表达。CT-1诱导心肌细胞肥大，保护心肌细胞免受缺血再灌注损伤。我们试图阐明心脏成纤维细胞中的CT-1信号与蛋白质合成的启动有关。方法：从200g级SD大鼠的脑室分离心脏成纤维细胞，用不同浓度的CT-1分别加或不加细胞信号通路抑制剂。Western分析和免疫细胞化学检测细胞内信号转导通路的激活。[(3)H]亮氨酸掺入法测定蛋白质合成。结果：CT-1处理导致Jak/STAT、MAPK和Akt信号通路的激活以及蛋白质合成调节蛋白的激活，从而导致总蛋白质合成增加。磷酸化特异性抗体分析表明，AG490(JAK抑制剂)、PD98059(MEK1/2抑制剂)、SB203580(p38 MAPK抑制剂)、LY294002(PI3-K抑制剂)和雷帕霉素(mTOR抑制剂)在不同程度上抑制CT-1诱导的蛋白质合成。结论：心肌营养素-1可激活心脏成纤维细胞的Jak/STAT、PI3K/Akt、p38和p42/44 MAPK信号通路。药物抑制剂的使用表明，这些途径中的每一个都在CT-1诱导的蛋白质合成中发挥作用。(C)2003年欧洲心脏病学会。爱思唯尔出版，版权所有。
Objective: Cardiotrophin-1 (CT- 1) is a member of the IL-6 family of cytokines and is expressed in various cardiovascular disease states. CT-1 induces cardiomyocyte hypertrophy, and protects myocytes from ischemia reperfusion injury. We sought to elucidate CT-1 signaling in cardiac fibroblasts with respect to initiation of protein synthesis. Methods: Cardiac fibroblasts were isolated from the ventricles of 200-g Sprague-Dawley rats and stimulated with CT-1 at specified concentrations with or without inhibitors of cell signaling pathways. Activation of intracellular signaling pathways was determined by Western analysis and immunocytochemistry. Protein synthesis was measured by incorporation of [(3)H]leucine. Results: CT-1 treatment resulted in activation of the Jak/STAT, MAPK, and Akt pathways in addition to protein synthesis regulatory proteins with resultant increase in overall protein synthesis. Analysis with phospho-specific antibodies revealed that AG490 (Jak inhibitor), PD98059 (MEK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), LY294002 (PI3-K inhibitor) and rapamycin (mTOR inhibitor) act at different levels in the signaling cascade to inhibit CT-1 induced protein synthesis. Conclusion: Cardiotrophin-1 activates the Jak/STAT, PI3K/Akt, p38 and p42/44 MAPK pathways in cardiac fibroblasts. Use of pharmacologic inhibitors reveals that each of these pathways play a role in CT-1 induced protein synthesis. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.