Extracellular signal-regulated protein kinase activation is required for the anti-hypertrophic effect of atrial natriuretic factor in neonatal rat ventricular myocytes

Michael Silberbach, Travis Gorenc, Ray E. Hershberger, Philip J.S. Stork, Peter S. Steyger, Charles T. Roberts

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Atrial natriuretic factor (ANF) inhibits proliferation in non-myocardial cells and is thought to be anti-hypertrophic in cardiomyocytes. We investigated the possibility that the anti-hypertrophic actions of ANF involved the mitogen-activated protein kinase signal transduction cascade. Cultured neonatal rat ventricular myocytes treated for 48 h with the α1- adrenergic agonist phenylephrine (PE) had an 80% increase in cross-sectional area (CSA). ANF alone had no effect but inhibited PE-induced increases in CSA by approximately 50%. The mitogen-activated protein kinase/ERK kinase (MEK) inhibitor PD098059 minimally inhibited PE-induced increases in CSA, but it completely abolished ANF-induced inhibition of PE-induced increases. AN-F- induced extracellular signal-regulated protein kinase (ERK) nuclear translocation was also eliminated by PD098059. ANF treatment caused MEK phosphorylation and activation but failed to activate any of the Raf isoforms. ANF induced a rapid increase in ERK phosphorylation and in vitro kinase activity. PE also increased ERK activity, and the combined effect of ANF and PE appeared to be additive. ANF-induced ERK phosphorylation was eliminated by PD098059. ANF induced minimal phosphorylation of JNK or p38, indicating that its effect on ERK was specific. ANF-induced activation of ERK was mimicked by cGMP analogs, suggesting that ANF-induced ERK activation involves the guanylyl cyclase activity of the ANF receptor. These data suggest that there is an important linkage between cGMP signaling and the mitogen-activated protein kinase cascade and that selective ANF activation of ERK is required for the anti-hypertrophic action of ANF. Thus, ANF expression might function as the natural defense of the heart against maladaptive hypertrophy through its ability to activate ERK.

Original languageEnglish (US)
Pages (from-to)24858-24864
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number35
DOIs
StatePublished - Aug 27 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Extracellular signal-regulated protein kinase activation is required for the anti-hypertrophic effect of atrial natriuretic factor in neonatal rat ventricular myocytes'. Together they form a unique fingerprint.

  • Cite this