Published Online
on December 22, 2008

A more recent version of this article appeared on January 6, 2009

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Submitted on April 15, 2008
Accepted on October 22, 2008

Critical Role of Transcription Factor Cyclic AMP Response Element Modulator in ₁-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, and 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.

^* To whom correspondence should be addressed. E-mail: mullerf{at}uni-muenster.de.

Background—Chronic stimulation of the ₁-adrenoceptor (₁AR) 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 ₁AR-mediated cardiac deterioration.

Methods and Results—We studied the role of CREM in ₁AR-mediated cardiac effects, comparing transgenic mice with heart-directed expression of ₁AR in the absence and presence of functional CREM. CREM inactivation protected from cardiomyocyte hypertrophy, fibrosis, and left ventricular dysfunction in ₁AR-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 ₁AR-transgenic hearts.

Conclusions—The results imply the regulation of genes by CREM as an important mechanism of ₁AR-induced cardiac damage in mice.

Key words: molecular biology • myocardium • receptors, adrenergic, beta

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