The mixed-lineage kinase 1-3 signalling pathway regulates stress response in cardiac myocytes via GATA-4 and AP-1

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A Ola1, R Kerkelä, H Tokola

  • 1Institute of Biomedicine, Department of Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, Oulu, Finland.

British Journal of Pharmacology
|January 14, 2010
PubMed
Abstract

Insights

Mixed-lineage kinase (MLK) inhibition suppresses cardiac hypertrophy by blocking key transcription factors. This study shows MLK1-3 inhibition reduces stress responses and cardiac gene activation in heart cells.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Signal Transduction

Background:

  • Mixed-lineage kinases (MLKs) are upstream regulators of mitogen-activated protein kinases (MAPKs).
  • The specific role of MLKs in cardiac physiology and pathology remains largely uncharacterized.

Purpose of the Study:

  • To investigate the impact of a mixed-lineage kinase 1-3 (MLK1-3) inhibitor, CEP-11004, on G protein-coupled receptor agonist-induced stress responses in neonatal rat cardiac myocytes.
  • To elucidate the downstream signaling pathways affected by MLK inhibition in the context of cardiac stress.

Main Methods:

  • Primary neonatal rat cardiac myocytes were cultured and treated with G protein-coupled receptor agonists (phenylephrine and endothelin-1).
  • The effects of CEP-11004 on c-Jun N-terminal kinase (JNK) and p38 MAPK phosphorylation were assessed.
  • Activator protein-1 (AP-1) and GATA-binding protein 4 (GATA-4) binding activities, as well as B-type natriuretic peptide (BNP) gene transcription, were measured.
  • Secretion of atrial natriuretic peptide (ANP) and BNP was quantified.

Main Results:

  • CEP-11004 dose-dependently attenuated phenylephrine and endothelin-1 (ET-1)-induced c-Jun N-terminal kinase (JNK) activation.
  • MLK inhibition reduced ET-1- and phenylephrine-induced p38 MAPK phosphorylation.
  • CEP-11004 administration significantly decreased ET-1- and phenylephrine-induced activator protein-1 (AP-1) binding activity.
  • MLK inhibition attenuated ET-1-induced GATA-binding protein 4 (GATA-4) binding activity and phenylephrine-induced B-type natriuretic peptide (BNP) gene transcription.
  • Agonist-induced secretion of atrial natriuretic peptide (ANP) and BNP was reduced by MLK inhibition.

Conclusions:

  • Inhibition of the MLK1-3 signaling pathway effectively suppresses key nuclear effectors, including GATA-4 and AP-1 transcription factors, in models of cardiac hypertrophy.
  • MLK1-3 inhibition attenuates agonist-induced atrial natriuretic peptide secretion and B-type natriuretic peptide gene transcription.
  • Targeting the MLK1-3 pathway represents a potential therapeutic strategy for mitigating cardiac hypertrophy.

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