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

J Mol Cell Cardiol. 2005 Jan;38(1):185-92. doi: 10.1016/j.yjmcc.2004.10.016. Epub 2004 Dec 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomegaly / enzymology*
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology*
  • Cells, Cultured
  • Cytokines / pharmacology*
  • DNA-Binding Proteins / metabolism
  • Flavonoids / pharmacology
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 5 / genetics
  • MAP Kinase Kinase 5 / metabolism*
  • MAP Kinase Signaling System / drug effects*
  • Mitogen-Activated Protein Kinase 7 / metabolism*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / metabolism
  • Phosphorylation
  • Rats
  • Rats, Wistar
  • STAT3 Transcription Factor
  • Trans-Activators / metabolism


  • Cytokines
  • DNA-Binding Proteins
  • Flavonoids
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Trans-Activators
  • cardiotrophin 1
  • Mitogen-Activated Protein Kinase 7
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 5
  • Map2k5 protein, rat
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one