Article,

Critical role of transcription factor cyclic AMP response element modulator in beta1-adrenoceptor-mediated cardiac dysfunction

, , , , , , , , , , , , , and .
Circulation, 119 (1): 79-88 (January 2009)Lewin, Geertje Matus, Marek Basu, Abhijit Frebel, Karin Rohsbach, Sebastian Pius Safronenko, Andrej Seidl, Matthias Dodo Stumpel, Frank Buchwalow, Igor Konig, Simone Engelhardt, Stefan Lohse, Martin J Schmitz, Wilhelm Muller, Frank Ulrich Research Support, Non-U.S. Gov't United States Circulation Circulation. 2009 Jan 6;119(1):79-88. Epub 2008 Dec 22..

Abstract

BACKGROUND: Chronic stimulation of the beta(1)-adrenoceptor (beta(1)AR) plays a crucial role in the pathogenesis of heart failure; however, underlying mechanisms remain to be elucidated. The regulation by transcription factors cAMP response element-binding protein (CREB) and cyclic AMP response element modulator (CREM) represents a fundamental mechanism of cyclic AMP-dependent gene control possibly implicated in beta(1)AR-mediated cardiac deterioration. METHODS AND RESULTS: We studied the role of CREM in beta(1)AR-mediated cardiac effects, comparing transgenic mice with heart-directed expression of beta(1)AR in the absence and presence of functional CREM. CREM inactivation protected from cardiomyocyte hypertrophy, fibrosis, and left ventricular dysfunction in beta(1)AR-overexpressing mice. Transcriptome and proteome analysis revealed a set of predicted CREB/CREM target genes including the cardiac ryanodine receptor, tropomyosin 1alpha, and cardiac alpha-actin as altered on the mRNA or protein level along with the improved phenotype in CREM-deficient beta(1)AR-transgenic hearts. CONCLUSIONS: The results imply the regulation of genes by CREM as an important mechanism of beta(1)AR-induced cardiac damage in mice.

Tags

Users

  • @pharmawuerz

Comments and Reviews