Cardiac Dysfunction

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. (Circulation. 2009;119:79-88.)