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Submitted on February 8, 2005
Accepted on July 8, 2005
1-adrenergic agonists
Cellular Biochemistry Laboratory, Baker Heart Research Institute, Commercial Road, Melbourne, 3004, Victoria, Australia
* To whom correspondence should be addressed. E-mail: liz.woodcock{at}baker.edu.au.
Apoptotic responses in cardiomyocytes are opposed by the protein kinase Akt (PKB) and thus can be suppressed by a number of growth factors and cytokines. In some cell types Akt phosphorylates and inactivates members of the FOXO (FKHR) family of transcription factors that are active in regulating the expression of pro-apoptotic cytokines and signaling intermediates. In the current study, we investigated the possibility that FOXO1 (FKHR) was expressed, regulated and functional in cardiomyocytes. Addition of epidermal growth factor (EGF) (10 nM) to neonatal rat cardiomyocytes caused rapid phosphorylation of Akt and slower FOXO1 phosphorylation. In contrast, the 
1-adrenergic receptor agonist, phenylephrine (50 µM), did not phosphorylate Akt and caused dephosphorylation of FOXO1 acutely and increased FOXO1 expression with chronic exposure. Phenylephrine, but not EGF, caused nuclear translocation of FOXO1, a response that is associated with dephosphorylation. Overexpression of FOXO1 activated transcription of the pro-apoptotic cytokine, TNF-related apoptosis inducing ligand (TRAIL), as indicated by reporter gene activity. This response was enhanced by phenylephrine and inhibited by EGF. FOXO1 is expressed, regulated and functionally active in cardiomyocytes and thus may contribute to apoptotic responses in heart.
1-adrenergic receptor •
Akt •
GSK3
•
TRAIL
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