Dynamic regulation of MEK/Erks and Akt/GSK-3? in human end-stage heart failure after left ventricular mechanical support: myocardial mechanotransduction-sensitivity as a possible molecular mechanism

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-3 beta, 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-3 beta 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-3 beta. CONCLUSION: Erks and Akt/GSK-3 beta are highly responsive to myocyte stretch in vitro and in vivo, and may be sensitive molecular parameters of 'reverse remodeling' under LVAD support.