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The mixed‐lineage kinase 1–3 signalling pathway regulates stress response in cardiac myocytes via GATA‐4 and AP‐1 transcription factors
Author(s) -
Ola A,
Kerkelä R,
Tokola H,
Pikkarainen S,
Skoumal R,
Vuolteenaho O,
Ruskoaho H
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00567.x
Subject(s) - atrial natriuretic peptide , protein kinase a , phenylephrine , kinase , endocrinology , activator (genetics) , medicine , biology , agonist , microbiology and biotechnology , chemistry , receptor , blood pressure
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.