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Regulation of the proapoptotic factor FOXO1 (FKHR) in cardiomyocytes by growth factors and alpha1-adrenergic agonists

James B Morris1, Bronwyn Kenney, Huy Huynh

  • 1Cellular Biochemistry Laboratory, Baker Heart Research Institute, PO Box 6492, St. Kilda Road Central, Melbourne 8009, Victoria, Australia.

Endocrinology
|July 16, 2005
PubMed

Insights

Forkhead box protein 1 (FOXO1) is active in heart cells and can promote apoptosis. Phenylephrine increases FOXO1 expression and nuclear localization, enhancing its pro-apoptotic function in cardiomyocytes.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cell Biology
  • Signaling Pathways

Background:

  • Cardiomyocyte apoptosis is regulated by protein kinase Akt, which can suppress cell death.
  • Akt phosphorylates forkhead box (FOXO) transcription factors, inhibiting their pro-apoptotic activity.
  • The role of FOXO1 in cardiomyocyte apoptosis was investigated.

Purpose of the Study:

  • To determine if FOXO1 is expressed, regulated, and functional in cardiomyocytes.
  • To investigate the effects of epidermal growth factor (EGF) and phenylephrine on FOXO1 activity.
  • To understand FOXO1's contribution to cardiomyocyte apoptosis.

Main Methods:

  • Neonatal rat cardiomyocytes were treated with EGF and phenylephrine.
  • Akt and FOXO1 phosphorylation, expression, and subcellular localization were assessed.
  • Reporter gene assays were used to measure FOXO1 transcriptional activity.
  • FOXO1's role in apoptosis was evaluated.

Main Results:

  • EGF rapidly phosphorylated Akt and slowly phosphorylated FOXO1.
  • Phenylephrine did not phosphorylate Akt but caused FOXO1 dephosphorylation and increased its expression.
  • Phenylephrine induced nuclear translocation of FOXO1, unlike EGF.
  • Overexpressed FOXO1 activated the pro-apoptotic TNFalpha-related apoptosis-inducing ligand, an effect modulated by EGF and phenylephrine.

Conclusions:

  • FOXO1 is expressed, regulated, and functionally active in cardiomyocytes.
  • Phenylephrine promotes FOXO1 activity and nuclear localization, potentially increasing apoptosis.
  • FOXO1 may play a significant role in mediating apoptotic responses in the heart.

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