Cardioprotective stimuli mediate phosphoinositide 3-kinase and phosphoinositide dependent kinase 1 nuclear accumulation in cardiomyocytes

Marta Rubio, Daniele Avitabile, Kimberlee Fischer, Gregory Emmanuel, Natalie Gude, Shigeki Miyamoto, Shikha Mishra, Eric M. Schaefer, Joan Heller Brown, Mark A. Sussman

Research output: Contribution to journalArticle

Abstract

The phosphoinositide 3-kinase (PI3K)/phosphoinositide dependent kinase 1 (PDK1) signaling pathway exerts cardioprotective effects in the myocardium through activation of key proteins including Akt. Activated Akt accumulates in nuclei of cardiomyocytes suggesting that biologically relevant targets are located in that subcellular compartment. Nuclear Akt activity could be potentiated in both intensity and duration by the presence of a nuclear-associated PI3K/PDK1 signaling cascade as has been described in other non-myocyte cell types. PI3K/PDK1 distribution was determined in vitro and in vivo by immunostaining and nuclear extraction of cultured rat neonatal cardiomyocytes or transgenic mouse hearts. Results show that PI3K and PDK1 are present at a basal level in cardiomyocytes nuclei and that cardioprotective stimulation with atrial natriuretic peptide (ANP) increases their nuclear localization. In comparison, overexpression of nuclear-targeted Akt does not mediate increased translocation of either PI3K or PDK1 indicating that accumulation of Akt does not drive PI3K or PDK1 into the nuclear compartment. Furthermore, PI3K and phospho-Akt473 show parallel temporal accumulation in the nucleus following (MI) infarction challenge. These findings demonstrate the presence of a dynamically regulated nuclear-associated signaling cascade involving PI3K and PDK that presumably influences nuclear Akt activation.

Original languageEnglish
Pages (from-to)96-103
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume47
Issue number1
DOIs
Publication statusPublished - Jul 2009

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Keywords

  • Akt
  • Cardiomyocyte
  • Nucleus
  • PDK1
  • Phosphoinositide
  • PI3K

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Rubio, M., Avitabile, D., Fischer, K., Emmanuel, G., Gude, N., Miyamoto, S., Mishra, S., Schaefer, E. M., Brown, J. H., & Sussman, M. A. (2009). Cardioprotective stimuli mediate phosphoinositide 3-kinase and phosphoinositide dependent kinase 1 nuclear accumulation in cardiomyocytes. Journal of Molecular and Cellular Cardiology, 47(1), 96-103. https://doi.org/10.1016/j.yjmcc.2009.02.022