Involvement of nuclear factor-kappaB and apoptosis signal-regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy

Circulation. 2002 Jan 29;105(4):509-15. doi: 10.1161/hc0402.102863.


Background: Recently, reactive oxygen species (ROS) have emerged as important molecules in cardiac hypertrophy. However, the ROS-dependent signal transduction mechanism remains to be elucidated. In this study, we examined the role of an ROS-sensitive transcriptional factor, NF-kappaB, and a mitogen-activated protein kinase kinase kinase, apoptosis signal-regulating kinase 1 (ASK1), in G-protein-coupled receptor (GPCR) agonist (angiotensin II, endothelin-1, phenylephrine)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes.

Methods and results: Using an ROS-sensitive fluorescent dye, we observed an increase in fluorescence signal on addition of the GPCR agonists. The GPCR agonists induced NF-kappaB activation. Antioxidants such as N-acetyl cysteine, N-mercaptopropionyl glycine, and vitamin E attenuated the NF-kappaB activation. Infection of cardiomyocytes with an adenovirus expressing a degradation-resistant mutant of IkappaBalpha led to suppression of the hypertrophic responses. The GPCR agonists rapidly and transiently activated ASK1 in a dose-dependent manner. Infection of an adenovirus expressing a dominant-negative ASK1 attenuated the GPCR agonist-induced NF-kappaB activation and cardiac hypertrophy. Overexpression of a constitutively active mutant of ASK1 led to NF kappaB activation and cardiac hypertrophy. Activated ASK1-induced hypertrophy was abolished by inhibition of NF-kappaB activation.

Conclusions: These data indicate that GPCR agonist-induced cardiac hypertrophy is mediated through NF-kappaB activation via the generation of ROS. ASK1 is involved in GPCR agonist-induced NF-kappaB activation and resulting hypertrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology
  • Animals
  • Cardiomegaly / etiology
  • Cell Size
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Endothelin-1 / pharmacology
  • Heterotrimeric GTP-Binding Proteins / metabolism*
  • I-kappa B Proteins / genetics
  • Kinetics
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases / physiology*
  • Mutation
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Myocardium / ultrastructure
  • NF-kappa B / physiology*
  • Phenylephrine / pharmacology
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Receptors, Cell Surface / agonists
  • Sarcomeres / ultrastructure


  • Endothelin-1
  • I-kappa B Proteins
  • NF-kappa B
  • Reactive Oxygen Species
  • Receptors, Cell Surface
  • Angiotensin II
  • Phenylephrine
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases
  • Heterotrimeric GTP-Binding Proteins