Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries

Sergio de Frutos, Juan Manuel Ramiro Diaz, Carlos H. Nitta, Mingma L. Sherpa, Laura V. Gonzalez Bosc

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Chronic hypoxia (CH) activates the Ca2 2+-dependent transcriptionfactor nuclear factor of activated T cells isoform c3 (NFATc3) in mouse pulmonary arteries. However, the mechanism of this response has not been explored. Since we have demonstrated that NFATc3 is required for CH-induced pulmonary arterial remodeling, establishing how CH activates NFATc3 is physiologically significant. The goal of this study was to test the hypothesis that endothelin-1 (ET-1) contributes to CH-induced NFATc3 activation. We propose that this mechanism requires increased pulmonary arterial smooth muscle cell (PASMC) intracellular Ca2 2+ concentration ([Ca2 2+]i) and stimulation of RhoA/Rho kinase (ROK), leading to calcineurin activation and actin cytoskeleton polymerization, respectively. We found that: 1) CH increases pulmonary arterial pre-pro-ET-1 mRNA expression and lung RhoA activity; 2) inhibition of ET receptors, calcineurin, L-type Ca 2+ channels, and ROK blunts CH-induced NFATc3 activation in isolated intrapulmonary arteries from NFAT-luciferase reporter mice; and 3) both ET-1-induced NFATc3 activation in isolated mouse pulmonary arteries ex vivo and ET-1-induced NFATc3-green fluorescence protein nuclear import in human PASMC depend on ROK and actin polymerization. This study suggests that CH increases ET-1 expression, thereby elevating PASMC [Ca2 2+]i and RhoA/ROK activity. As previously demonstrated, elevated [Ca2 2+]i is required to activate calcineurin, which dephosphorylates NFATc3, allowing its nuclear import. Here, we demonstrate that ROK increases actin polymerization, thus providing structural support for NFATc3 nuclear transport.

Original languageEnglish (US)
Pages (from-to)C441-C450
JournalAmerican Journal of Physiology - Cell Physiology
Volume301
Issue number2
DOIs
StatePublished - Aug 2011

Keywords

  • Cytoskeletal dynamics
  • Nuclear factor of activated T cells isoform c3
  • Pulmonary
  • Rho kinase
  • Smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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