Critical role of transcription factor cyclic AMP response element modulator in β1-adrenoceptor-mediated cardiac dysfunction

Abstract

Background-Chronic stimulation of the β1radrenoceptor (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 lα, and cardiac α-actin as altered on the mRNA or protein level along with the improved phenotype in CREM-deficient β1R-transgenic hearts. Conclusions-The results imply the regulation of genes by CREM as an important mechanism of β1AR- induced cardiac damage in mice. (Circulation. 2009;119:79-88.) © 2009 American Heart Association, Inc.