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

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47 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)185-192
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume38
Issue number1
DOIs
Publication statusPublished - 2005 Jan 1
Externally publishedYes

Keywords

  • Cardiomyocyte
  • Cardiotrophin-1
  • Cell signaling
  • Cytokine
  • ERK1/2
  • ERK5
  • Hypertrophy
  • STAT3

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    Takahashi, N., Saito, Y., Kuwahara, K., Harada, M., Tanimoto, K., Nakagawa, Y., Kawakami, R., Nakanishi, M., Yasuno, S., Usami, S., Yoshimura, A., & Nakao, K. (2005). Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes. Journal of Molecular and Cellular Cardiology, 38(1), 185-192. https://doi.org/10.1016/j.yjmcc.2004.10.016