title: Suppression of cardiomyocyte hypertrophy by inhibition of the ubiquitin-proteasome system.
abstract: Inhibitors of the proteasome interfere with transcriptional regulation of growth signaling pathways and block cell cycle progression of mitotic cells. As growth signaling pathways are highly conserved between mitotic and postmitotic cells, we hypothesized that proteasome inhibition might also be a valuable approach to interfere with hypertrophic growth of postmitotic cardiomyocytes. To test this hypothesis, we analyzed the effects of proteasome inhibition on hypertrophic growth of neonatal rat cardiomyocytes. Partial inhibition of the proteasome effectively suppressed cardiomyocyte hypertrophy as determined by reduced cell size, inhibition of hypertrophy-mediated induction of RNA and protein synthesis, reduced expression of several hypertrophic marker genes, and diminished transcriptional activation of the BNP promotor. Importantly, suppression of hypertrophic growth was independent of the hypertrophic agonist used. Expressional profiling and subsequent Western blot and kinase assays revealed that proteasome inhibition induced a cellular stress response with reduced expression of conserved growth signaling mediators and impaired G1/S phase transition of cardiomyocytes. In hypertensive Dahl-salt sensitive rats, inhibition of the proteasome with low doses of the FDA approved proteasome inhibitor Velcade significantly reduced hypertrophic heart growth. Our data provide important insight into the suppressive effects of proteasome inhibitors on hypertrophic growth of cardiomyocytes and establish low-dose proteasome inhibition as a new and broad-spectrum approach to interfere with cardiac hypertrophy.
authors: Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors: Silke
authors: S
authors: Meiners
authors: Henryk
authors: H
authors: Dreger
authors: Mandy
authors: M
authors: Fechner
authors: Sven
authors: S
authors: Bieler
authors: Wim
authors: W
authors: Rother
authors: Christoph
authors: C
authors: Günther
authors: Gert
authors: G
authors: Baumann
authors: Verena
authors: V
authors: Stangl
authors: Karl
authors: K
authors: Stangl
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006984:Hypertrophy / Q000378:metabolism / Q000517:prevention & control; D007976:Leupeptins / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D061988:Proteasome Inhibitors; D051381:Rats; D020303:Rats, Inbred Dahl; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000037:antagonists & inhibitors*
chemical_list: D015415:Biomarkers; D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; C423917:MG 262; D061988:Proteasome Inhibitors; D025801:Ubiquitin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde