Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes

Nobuki Takahashi, Yoshihiko Saito, Koichiro Kuwahara, Masaki Harada, Keiji Tanimoto, Yasuaki Nakagawa, Rika Kawakami, Michio Nakanishi, Shinji Yasuno, Satoru Usami, Akihiko Yoshimura, Kazuwa Nakao

研究成果: Article査読

48 被引用数 (Scopus)


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.

ジャーナルJournal of Molecular and Cellular Cardiology
出版ステータスPublished - 2005 1月

ASJC Scopus subject areas

  • 分子生物学
  • 循環器および心血管医学


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