title: Mechanical unloading of the failing human heart fails to activate the protein kinase B/Akt/glycogen synthase kinase-3beta survival pathway.
abstract: BACKGROUND
  Left ventricular assist device (LVAD) support of the failing human heart improves myocyte function and increases cell survival. One potential mechanism underlying this phenomenon is activation of the protein kinase B (PKB)/Akt/glycogen synthase kinase-3beta (GSK-3beta) survival pathway.
  
  
  RESULTS
  Left ventricular tissue was obtained both at the time of implantation and explantation of the LVAD (n = 11). Six patients were diagnosed with idiopathic dilated cardiomyopathy, 4 patients with ischemic cardiomyopathy and 1 patient with peripartum cardiomyopathy. The mean duration of LVAD support was 205 +/- 35 days. Myocyte diameter and phosphorylation of ERK were used as indices for reverse remodeling. Transcript levels of genes required for the activation of PKB/Akt (insulin-like growth factor-1, insulin receptor substrate-1) were measured by quantitative RT-PCR. In addition, we measured the relative activity of PKB/Akt and GSK-3beta, and assayed for molecular and histological indices of PKB/Akt activation (cyclooxygenase mRNA levels and glycogen levels). Myocyte diameter and phosphorylation of ERK decreased with LVAD support. In contrast, none of the components of the PKB/Akt/GSK-3beta pathway changed significantly with mechanical unloading.
  
  
  CONCLUSIONS
  The PKB/Akt/GSK-3beta pathway is not activated during LVAD support. Other signaling pathways must be responsible for the improvement of cellular function and cell survival during LVAD support.
authors.affiliation: Division of Cardiology, University of Texas-Houston Medical School, Houston, TX 77030, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Razeghi
authors.forename: Brian A
authors.initials: BA
authors.lastname: Bruckner
authors.forename: Saumya
authors.initials: S
authors.lastname: Sharma
authors.forename: Keith A
authors.initials: KA
authors.lastname: Youker
authors.forename: O H
authors.initials: OH
authors.lastname: Frazier
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
mesh_terms: D000199:Actins / Q000235:genetics; D000328:Adult; D002470:Cell Survival; D051546:Cyclooxygenase 2; D004789:Enzyme Activation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D006352:Heart Ventricles / Q000473:pathology; D006353:Heart-Assist Devices; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D000199:Actins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017526:Receptor, IGF Type 1; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3