Critical Role of Transcription Factor Cyclic AMP Response Element Modulator in β 1 -Adrenoceptor–Mediated Cardiac Dysfunction

Abstract

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