© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Dynamic regulation of MEK/Erks and Akt/GSK-3β in human end-stage heart failure after left ventricular mechanical support: myocardial mechanotransduction-sensitivity as a possible molecular mechanism
aInstitute of Pathology, University of Essen, Essen, Germany
bDepartment of Internal Medicine, Jikei University, Tokyo, Japan
cDepartment of Cardiology and Angiology, University of Münster, Münster, Germany
dDepartment of Thoracic and Cardiovascular Surgery, University of Münster, Münster, Germany
eDepartment of Nuclear Medicine, University of Münster, Münster, Germany
fInstitute of Pathology, University of Münster, Münster, Germany
gDepartment of Molecular Cardiology, Institute of Arteriosclerosis Research, University of Münster, 48149 Münster, Germany
* Corresponding author. Tel.: +49-251-835-8625; fax: +49-251-836-6088. levkau{at}uni-muenster.de
Objective: Left ventricular assist devices (LVAD) are used to ‘bridge’ patients with end-stage heart failure to transplantation. After long-term LVAD support, ventricular function may partially recover, a process called ‘reverse remodeling’. As several kinase-mediated signal transduction pathways have been implicated in the development of cardiac hypertrophy and failure, we examined the activities of the Erks, MEKs, Akt, GSK-3β, p70S6K, JNKs and p38 under LVAD support as well as during single myocyte strain and whole heart stretch. Methods: Western blotting and immunohistochemistry were performed using phospho-specific antibodies in matched samples from ten patients with end-stage heart failure before and after LVAD. Cyclic strain was performed in rat neonatal cardiac myocytes, and tensile stretch applied to Langendorff-perfused mouse hearts via a left ventricular balloon. Results: The activity of Erks and Akt in failing hearts dramatically decreased after LVAD support, while that of GSK-3β increased. There was an endo/epicardial gradient for Erk activity which persisted after LVAD despite the reduction of total Erk activity. TUNEL-positivity and myocyte size decreased after LVAD, but independently of changes in kinase activity. In cardiomyocytes and Langendorff-perfused mouse hearts both strain/stretch and its relief regulated the activities of Erks, Akt, and GSK-3β. Conclusion: Erks and Akt/GSK-3β are highly responsive to myocyte stretch in vitro and in vivo, and may be sensitive molecular parameters of ‘reverse remodeling’ under LVAD support.
KEYWORDS Heart failure; Remodeling; Mechanotransduction; Protein kinases; Apoptosis; Stretch
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