title: Cardioprotective stimuli mediate phosphoinositide 3-kinase and phosphoinositide dependent kinase 1 nuclear accumulation in cardiomyocytes.
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-Akt(473) 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.
authors.affiliation: SDSU Heart Institute, Department of Biology, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA. sussman@heart.sdsu.edu
authors.forename: Marta
authors.initials: M
authors.lastname: Rubio
authors.forename: Daniele
authors.initials: D
authors.lastname: Avitabile
authors.forename: Kimberlee
authors.initials: K
authors.lastname: Fischer
authors.forename: Gregory
authors.initials: G
authors.lastname: Emmanuel
authors.forename: Natalie
authors.initials: N
authors.lastname: Gude
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Shikha
authors.initials: S
authors.lastname: Mishra
authors.forename: Eric M
authors.initials: EM
authors.lastname: Schaefer
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000494:pharmacology; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology; D051381:Rats
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C578564:Pdpk1 protein, mouse; C578579:Pdpk1 protein, rat