Published Online
on December 17, 2007

A more recent version of this article appeared on February 1, 2008

This Article Full Text (PDF) Data Supplement All Versions of this Article: 51/2/302    most recent HYPERTENSIONAHA.107.097816v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Meiners, S. Articles by Stangl, K. Search for Related Content PubMed PubMed Citation Articles by Meiners, S. Articles by Stangl, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Animal models of human disease Cell signalling/signal transduction Gene expression Hypertrophy

Submitted on July 23, 2007
Revised on August 8, 2007

Suppression of Cardiomyocyte Hypertrophy by Inhibition of the Ubiquitin-Proteasome System

Silke Meiners; Henryk Dreger; Mandy Fechner; Sven Bieler; Wim Rother; Christoph Günther; Gert Baumann; Verena Stangl; and Karl Stangl^*

From the Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité - Universitaetsmedizin Berlin, Germany.

^* To whom correspondence should be addressed. E-mail: karl.stangl{at}charite.de.

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.

Key words: hypertrophy • stress • gene expression • myocytes • molecular biology

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