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

A. Ola, R. Kerkelä, H. Tokola, S. Pikkarainen, R. Skoumal, O. Vuolteenaho, H. Ruskoaho

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6 Citations (Scopus)

Abstract

Background and purpose: The mixed-lineage kinases (MLKs) act upstream of mitogen-activated protein kinases, but their role in cardiac biology and pathology is largely unknown. Experimental approach: We investigated the effect of a MLK1-3 inhibitor CEP-11004 on G protein-coupled receptor agonist-induced stress response in neonatal rat cardiac myocytes in culture. Key results: CEP-11004 administration dose-dependently attenuated phenylephrine and endothelin-1 (ET-1)-induced c-Jun N-terminal kinase activation. MLK inhibition also reduced ET-1- and phenylephrine-induced phosphorylation of p38 mitogen-activated protein kinase. In contrast, phenylephrine-induced extracellular signal-regulated kinase phosphorylation was further up-regulated by CEP-11004. ET-1 increased activator protein-1 binding activity 3.5-fold and GATA-binding protein 4 (GATA-4) binding activity 1.8-fold, both of which were attenuated with CEP-11004 administration by 59% and 63% respectively. Phenylephrine induced activator protein-1 binding activity by 2.6-fold, which was decreased by 81% with CEP-11004 administration. Phenylephrine also induced a 3.7-fold increase in the transcriptional activity of B-type natriuretic peptide (BNP), which was attenuated by 41% with CEP-11004 administration. In agreement, MLK inhibition also reduced hypertrophic agonist-induced secretion of immunoreactive atrial natriuretic peptide and BNP. Conclusions and implications: These results showed that inhibition of the MLK1-3 signalling pathway was sufficient for suppressing the activity of key nuclear effectors (GATA-4 and activator protein-1 transcription factors) in cardiac hypertrophy, and attenuated the agonist-induced atrial natriuretic peptide secretion and activation of BNP gene transcription.

Original languageEnglish
Pages (from-to)717-725
Number of pages9
JournalBritish journal of pharmacology
Volume159
Issue number3
DOIs
Publication statusPublished - Feb 1 2010

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Keywords

  • AP-1
  • CEP-11004
  • Cardiac hypertrophy
  • GATA-4
  • GPCR agonists
  • MLK

ASJC Scopus subject areas

  • Pharmacology

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