title: Dynamic regulation of MEK/Erks and Akt/GSK-3beta in human end-stage heart failure after left ventricular mechanical support: myocardial mechanotransduction-sensitivity as a possible molecular mechanism.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Pathology, University of Essen, Essen, Germany.
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Florian
authors.initials: F
authors.lastname: Grabellus
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
authors.forename: Andrea
authors.initials: A
authors.lastname: Sokoll
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takeda
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Wilhelm
authors.forename: Hans H
authors.initials: HH
authors.lastname: Scheld
authors.forename: Nobuakira
authors.initials: N
authors.lastname: Takeda
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006333:Heart Failure / Q000378:metabolism* / Q000628:therapy; D006353:Heart-Assist Devices; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical
chemical_list: D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases