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

Background: Chronic stimulation of the ß1-adrenoceptor (ß1AR) 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 ß1AR-mediated cardiac deterioration. Methods and Results: We studied the role of CREM in ß1AR-mediated cardiac effects, comparing transgenic mice with heart-directed expression of ß1AR in the absence and presence of functional CREM. CREM inactivation protected from cardiomyocyte hypertrophy, fibrosis, and left ventricular dysfunction in ß1AR-overexpressing mice. Transcriptome and proteome analysis revealed a set of predicted CREB/CREM target genes including the cardiac ryanodine receptor, tropomyosin 1{alpha}, and cardiac {alpha}-actin as altered on the mRNA or protein level along with the improved phenotype in CREM-deficient ß1AR-transgenic hearts. Conclusions: The results imply the regulation of genes by CREM as an important mechanism of ß1AR-induced cardiac damage in mice.