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

Research output: Contribution to journalArticle

45 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
Externally publishedYes

Fingerprint

Cardiac Myocytes
Hypertrophy
Phosphorylation
Janus Kinases
cardiotrophin 1
Cytokines
MAP Kinase Signaling System
Brain Natriuretic Peptide
Transducers
Heart Failure

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes. / Takahashi, Nobuki; Saito, Yoshihiko; Kuwahara, Koichiro; Harada, Masaki; Tanimoto, Keiji; Nakagawa, Yasuaki; Kawakami, Rika; Nakanishi, Michio; Yasuno, Shinji; Usami, Satoru; Yoshimura, Akihiko; Nakao, Kazuwa.

In: Journal of Molecular and Cellular Cardiology, Vol. 38, No. 1, 01.2005, p. 185-192.

Research output: Contribution to journalArticle

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, vol. 38, no. 1, pp. 185-192. https://doi.org/10.1016/j.yjmcc.2004.10.016
Takahashi, Nobuki ; Saito, Yoshihiko ; Kuwahara, Koichiro ; Harada, Masaki ; Tanimoto, Keiji ; Nakagawa, Yasuaki ; Kawakami, Rika ; Nakanishi, Michio ; Yasuno, Shinji ; Usami, Satoru ; Yoshimura, Akihiko ; Nakao, Kazuwa. / Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes. In: Journal of Molecular and Cellular Cardiology. 2005 ; Vol. 38, No. 1. pp. 185-192.
@article{4a2800ce03874d608b6b4de4e65b3011,
title = "Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes",
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.",
keywords = "Cardiomyocyte, Cardiotrophin-1, Cell signaling, Cytokine, ERK1/2, ERK5, Hypertrophy, STAT3",
author = "Nobuki Takahashi and Yoshihiko Saito and Koichiro Kuwahara and Masaki Harada and Keiji Tanimoto and Yasuaki Nakagawa and Rika Kawakami and Michio Nakanishi and Shinji Yasuno and Satoru Usami and Akihiko Yoshimura and Kazuwa Nakao",
year = "2005",
month = "1",
doi = "10.1016/j.yjmcc.2004.10.016",
language = "English",
volume = "38",
pages = "185--192",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes

AU - Takahashi, Nobuki

AU - Saito, Yoshihiko

AU - Kuwahara, Koichiro

AU - Harada, Masaki

AU - Tanimoto, Keiji

AU - Nakagawa, Yasuaki

AU - Kawakami, Rika

AU - Nakanishi, Michio

AU - Yasuno, Shinji

AU - Usami, Satoru

AU - Yoshimura, Akihiko

AU - Nakao, Kazuwa

PY - 2005/1

Y1 - 2005/1

N2 - 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.

AB - 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.

KW - Cardiomyocyte

KW - Cardiotrophin-1

KW - Cell signaling

KW - Cytokine

KW - ERK1/2

KW - ERK5

KW - Hypertrophy

KW - STAT3

UR - http://www.scopus.com/inward/record.url?scp=19944380417&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=19944380417&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2004.10.016

DO - 10.1016/j.yjmcc.2004.10.016

M3 - Article

VL - 38

SP - 185

EP - 192

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

IS - 1

ER -