Mechanical unloading of the failing human heart fails to activate the protein kinase B/Akt/glycogen synthase kinase-3β survival pathway

Peter Razeghi, Brian A. Bruckner, Saumya Sharma, Keith A. Youker, O. H. Frazier, Heinrich Taegtmeyer

Research output: Contribution to journalArticle

24 Scopus citations

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-3β) survival pathway. Methods and 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-3β, 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-3β pathway changed significantly with mechanical unloading. Conclusion: The PKB/Akt/GSK-3β 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.

Original languageEnglish (US)
Pages (from-to)17-22
Number of pages6
JournalCardiology
Volume100
Issue number1
DOIs
StatePublished - 2003

Keywords

  • Cell survival
  • Heart failure
  • Left ventricular assist device
  • Quantitative RT-PCR

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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