Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes.
Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes.
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DOI：
10.1016/j.yjmcc.2004.10.016
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发表时间：
2005
影响因子：
5
通讯作者：
N. Takahashi;Yoshihiko Saito;K. Kuwahara;M. Harada;K. Tanimoto;Y. Nakagawa;Rika Kawakami;M. Nakanishi;S. Yasuno;S. Usami;A. Yoshimura;K. Nakao
中科院分区：
文献类型：
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作者：
N. Takahashi;Yoshihiko Saito;K. Kuwahara;M. Harada;K. Tanimoto;Y. Nakagawa;Rika Kawakami;M. Nakanishi;S. Yasuno;S. Usami;A. Yoshimura;K. Nakao
已知GP 130依赖性信号传导在心力衰竭的发作中起关键作用。在这方面，心肌营养素-1（CT-1）通过gp 130激活几个信号通路，并诱导新生大鼠心肌细胞肥大。在CT-1激活的介质中，STAT 3被认为是诱导细胞肥大的重要因素，尽管其在CT-1信号通路中的确切功能尚未完全了解。因此，在本研究中，为了更好地理解STAT 3活性在CT-1信号传导中的意义，我们用腺病毒载体感染培养的心肌细胞，腺病毒载体携带显性负性STAT 3突变体或通过Janus激酶（JAK）-信号转导子和转录激活子（STAT）途径的细胞因子信号传导的两种内源性负性调节因子之一[细胞因子信号传导抑制因子（SOCS）1和3]。观察其对CT-1诱导的细胞肥大的蛋白质合成、脑钠肽分泌和细胞表面积变化三项指标的影响。在对照细胞中，CT-1诱导STAT 3磷酸化和细胞肥大。过表达显性负性STAT 3突变体抑制CT-1诱导的STAT 3磷酸化，但不影响细胞肥大。另一方面，SOCS 1或SOCS 3的过表达抑制CT-1诱导的STAT 3磷酸化和细胞肥大。CT-1还诱导心肌细胞中ERK 1/2和ERK 5的磷酸化，并且这些磷酸化也被SOCSs的过表达抑制。CT-1诱导的细胞肥大抑制显性阴性MEK 5突变体的过表达，而不是显性阴性MEK 1突变体的过表达。这些结果表明，负责对CT-1的肥大反应的主要途径不是JAK-STAT 3途径，也不是MEK 1-ERK 1/2途径，而是MEK 5-ERK 5途径。
gp130-dependent signaling is known to play a critical role in the onset of heart failure. In that regard, cardiotrophin-1 (CT-1) activates several signaling pathways via gp130, and induces hypertrophy in neonatal rat cardiomyocytes. Among the mediators activated by CT-1, STAT3 is thought to be important for induction of cell hypertrophy, though its precise function in the CT-1 signaling pathway is not fully understood. In the present study, therefore, to better understand the significance of STAT3 activity in CT-1 signaling, we infected cultured cardiomyocytes with adenoviral vectors harboring a dominant-negative STAT3 mutant or one of two endogenous negative regulators of cytokine signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways [suppressor of cytokine signaling (SOCS) 1 and 3] and then examined their effects on three indexes of CT-1-induced cell hypertrophy: protein synthesis, secretion of brain natriuretic peptide and changes in cell surface area. In control cells, CT-1-induced both STAT3 phosphorylation and cell hypertrophy. Overexpression of dominant-negative STAT3 mutant suppressed CT-1-induced STAT3 phosphorylation, but did not affect cell hypertrophy. On the other hand overexpression of SOCS1 or SOCS3 inhibited both CT-1-induced STAT3 phosphorylation and cell hypertrophy. CT-1 also induced phosphorylations of ERK1/2 and ERK5 in cardiomyocytes, and those, too, were suppressed by overexpression of SOCSs. CT-1-induced cell hypertrophy was suppressed by overexpression of a dominant-negative MEK5 mutant, and not by overexpression of a dominant-negative MEK1 mutant. These findings indicate that the major pathway responsible for the hypertrophic responses to CT-1 is not JAK-STAT3 pathway nor MEK1-ERK1/2 pathway, but MEK5-ERK5 pathway.