Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes
Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes
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DOI：
10.1161/01.cir.98.4.346
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发表时间：
1998-07-28
期刊：
影响因子：
37.8
通讯作者：
Kishimoto, T
中科院分区：
文献类型：
--
作者：
Kunisada, K;Tone, E;Kishimoto, T
背景-gp 130是IL-6相关细胞因子的信号转导子，广泛表达于包括心脏在内的组织中。据报道，心肌细胞中gp 130的激活可诱导心肌肥大。gp 130的下游侧在心肌细胞中由两个不同的通路组成，一个是Janus激酶/信号转导和转录激活因子（JAK/STAT）通路，另一个是丝裂原活化蛋白激酶（MAPK）通路。在本研究中，我们通过将野生型和突变型STAT 3 cDNA转染到心肌细胞中，来检测JAK/STAT通路，尤其是STAT 3介导的通路，是否在gp 130依赖性心肌肥大中起关键作用。携带野生型（AD/WT）或突变型（AD/DN）STAT 3 cDNA的复制缺陷型腺病毒载体或腺病毒载体本身（AD）。用白血病抑制因子（LIF）刺激腺病毒感染的培养小鼠心肌细胞，检测c-Sos和心钠素（ANF）mRNA的表达及[H-3]亮氨酸掺入。三组间MAPK活性无显著差异。与AD转染的心肌细胞相比，AD/WT转染的细胞在LIF刺激后c-Sos和ANF mRNA的诱导和蛋白质合成显著增加。与此相反，诱导c-Sos和心钠素mRNA的表达和蛋白质的合成减弱后，LIF刺激转染AD/DN的心肌细胞。结论这些结果表明，STAT 3依赖性信号通路下游的糖蛋白130促进心肌细胞肥大与LIF刺激下。
Background-gp130, a signal transducer of the IL-6-related cytokines, is expressed ubiquitously, including in the heart. The activation of gp130 in cardiac myocytes was reported to induce myocardial hypertrophy. The downstream side of gp130 consists of two distinct pathways in cardiac myocytes, one a Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, the other a mitogen-activated protein kinase (MAPK) pathway. In the present study, we examined whether the JAK/STAT pathway, especially the STAT3-mediated pathway, plays a critical role in gp130-dependent myocardial hypertrophy by transfecting wild-type and mutated-type STAT3 cDNA to cardiac myocytes.Methods and Results-We constructed three I;inds of replication-defective adenovirus vectors carrying wild-type (AD/WT) or mutated-type (AD/DN) STAT3 cDNA or adenovirus vector itself (AD). Cultured murine cardiac myocytes infected with adenovirus were stimulated with leukemia inhibitory factor (LIF), and the expression of c-Sos and atrial natriuretic factor (ANF) mRNAs and [H-3]leucine incorporation were examined. There were no significant differences in MAPK activity among the three groups. Compared with AD-transfected cardiac myocytes, induction of c-Sos and ANF mRNAs and protein synthesis after LIF stimulation were significantly augmented in AD/WT-transfected cells. In contrast, induction of c-Sos and ANF mRNA expression and protein synthesis were attenuated after LIF stimulation in cardiac myocytes transfected with AD/DN.Conclusions-These results suggest that the STAT3-dependent signaling pathway downstream of gp 130 promotes cardiac myocyte hypertrophy under stimulation with LIF.