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(Circulation. 2009;119:79-88.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Critical Role of Transcription Factor Cyclic AMP Response Element Modulator in β₁-Adrenoceptor–Mediated Cardiac Dysfunction

Geertje Lewin, PhD^*; Marek Matus, PhD, PharmDr^*; Abhijit Basu, MSc; Karin Frebel, PhD; Sebastian Pius Rohsbach; Andrej Safronenko, MD; Matthias Dodo Seidl, PhD; Frank Stümpel; Igor Buchwalow, PhD; Simone König, PhD; Stefan Engelhardt, MD, PhD; Martin J. Lohse, MD; Wilhelm Schmitz, MD; Frank Ulrich Müller, MD

From the Institute of Pharmacology and Toxicology (G.L., M.M., A.B., K.F., S.P.R., A.S., M.D.S., F.S., W.S., F.U.M.), Institute of Pathology (I.B.), and Core Unit Integrated Functional Genomics, Interdisciplinary Center for Clinical Studies (S.K.), University of Münster, Münster, Germany; and Rudolf-Virchow Center, DFG–Center for Experimental Biomedicine (S.E.), and Institute of Pharmacology (M.J.L.), University of Würzburg, Würzburg, Germany. Dr Lewin is currently affiliated with the Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.

Correspondence to Frank U. Müller, MD, Institute of Pharmacology and Toxicology, University of Münster, Domagkstrasse 12, D-48149 Münster, Germany. E-mail mullerf{at}uni-muenster.de

Received April 15, 2008; accepted October 22, 2008.

Background— Chronic stimulation of the β₁-adrenoceptor (β₁AR) 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 β₁AR-mediated cardiac deterioration.

Methods and Results— We studied the role of CREM in β₁AR-mediated cardiac effects, comparing transgenic mice with heart-directed expression of β₁AR in the absence and presence of functional CREM. CREM inactivation protected from cardiomyocyte hypertrophy, fibrosis, and left ventricular dysfunction in β₁AR-overexpressing mice. Transcriptome and proteome analysis revealed a set of predicted CREB/CREM target genes including the cardiac ryanodine receptor, tropomyosin 1, and cardiac -actin as altered on the mRNA or protein level along with the improved phenotype in CREM-deficient β₁AR-transgenic hearts.

Conclusions— The results imply the regulation of genes by CREM as an important mechanism of β₁AR-induced cardiac damage in mice.

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