Journal
CARDIOVASCULAR RESEARCH
Volume 59, Issue 2, Pages 390-399Publisher
OXFORD UNIV PRESS
DOI: 10.1016/S0008-6363(03)00393-6
Keywords
heart failure; remodeling; mechanotransduction; protein kinases; apoptosis; stretch
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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-3beta, 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-3beta 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-3beta. Conclusion: Erks and Akt/GSK-3beta are highly responsive to myocyte stretch in vitro and in vivo, and may be sensitive molecular parameters of 'reverse remodeling' under LVAD support. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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