Mechanism of endothelin-1 activation of map kinases in neonatal pulmonary vascular smooth muscle

Scott A Barman, Mario B Marrero

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Mitogen-activated protein kinases (MAPKs) belong to the group of serine-threonine kinases that are rapidly activated in response to growth factor stimulation. In adult mammalian cells, the MAPK family includes extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2 or p44 mapk and p42 mapk ), which translocate to the nucleus and integrate signals from second messengers leading to cellular proliferation or differentiation, but the specific role of MAPKs in neonatal pulmonary vascular smooth muscle is not well understood. Expression of p44 mapk and p42 mapk in primary cultured pulmonary vascular smooth muscle cells from neonatal (1-2 day old) rats was identified by Western immunoblot analysis and treatment with 10 nM endothelin-1 (ET-1), a potent vasoconstrictor with vascular mitogenic properties, induced cell proliferation, and phosphorylation of both p44 mapk and p42 mapk . The protein kinase C (PKC) isozyme inhibitor (α, β, γ, δ, ζ) Go 6983, the ET A receptor antagonist BQ 123, and the MAPK kinase inhibitor PD98059 blocked the cell proliferation response to ET-1. Also, BQ 123, Go 6983, and PKC inhibitor 20-28 (Myr-N-FARKGAL-RQ-NH 2 -PKCα antagonist) inhibited ET-1-induced phosphorylation of both p44 mapk and p42 mapk . In contrast, the reactive oxygen species (ROS) inhibitor diphenylene iodonium (DPI), the PKCδ inhibitor rottlerin, and the ET B receptor antagonist BQ 788 did not block ET-1-induced phosphorylation of MAPKs. Collectively, these data demonstrate the expression and phosphorylation of MAPKs by ET-1 and suggests that MAPK activation and cell proliferation by ET-1 occurs via ET A receptor stimulation and specific PKC isozyme activation in rat neonatal pulmonary vascular smooth muscle.

Original languageEnglish (US)
Pages (from-to)425-439
Number of pages15
JournalLung
Volume183
Issue number6
DOIs
Publication statusPublished - Dec 1 2005

    Fingerprint

Keywords

  • Endothelin-1
  • Mitogen-activated protein kinase
  • Neonatal
  • PKC isozymes
  • Pulmonary vascular smooth muscle

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this