Transforming growth factor-beta induces the expression of ANF and hypertrophic growth in cultured cardiomyoblast cells through ZAK

Biochem Biophys Res Commun. 2004 Nov 5;324(1):424-31. doi: 10.1016/j.bbrc.2004.09.067.

Abstract

Transforming growth factor-beta (TGF-beta) has been associated with the onset of cardiac cell hypertrophy, but the mechanisms underlying this dissociation are not completely understood. By a previous study, we investigated the involvement of a MAP3K, ZAK, which in cultured H9c2 cardiac cells is a positive mediator of cell hypertrophy. Our results showed that expression of a dominant-negative form of ZAK inhibited the characteristic TGF-beta-induced features of cardiac hypertrophy, including increased cell size, elevated expression of atrial natriuretic factor (ANF), and increased organization of actin fibers. Furthermore, dominant-negative MKK7 effectively blocked both TGF-beta-and ZAK-induced ANF expression. In contrast, a JNK/SAPK specific inhibitor, sp600125, had little effect on TGF-beta- or ZAK-induced ANF expression. Our findings suggest that a ZAK mediates TGF-beta-induced cardiac hypertrophic growth via a novel TGF-beta signaling pathway that can be summarized as TGF-beta>ZAK>MKK7>ANF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Angiotensin II / pharmacology
  • Animals
  • Anthracenes / pharmacology
  • Atrial Natriuretic Factor / genetics
  • Atrial Natriuretic Factor / metabolism*
  • Cell Size*
  • Cells, Cultured
  • Humans
  • Hypertrophy*
  • Interleukins / pharmacology
  • MAP Kinase Kinase 7 / genetics
  • MAP Kinase Kinase 7 / metabolism
  • MAP Kinase Kinase Kinases
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / pathology*
  • Myocytes, Cardiac / physiology*
  • Phenylephrine / pharmacology
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Rats
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology
  • Transforming Growth Factor beta / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism
  • Vasoconstrictor Agents / pharmacology

Substances

  • Actins
  • Anthracenes
  • Interleukins
  • Protein Kinase Inhibitors
  • Recombinant Fusion Proteins
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Vasoconstrictor Agents
  • Angiotensin II
  • pyrazolanthrone
  • Phenylephrine
  • Atrial Natriuretic Factor
  • Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP3K20 protein, human
  • MAP Kinase Kinase 7
  • MAP2K7 protein, human