The transcriptional activation mediated by cAMP-response element (CRE) and transcription factors of the CRE-binding protein (CREB)/CRE modulator (CREM) family represents an important mechanism of cAMP-dependent gene regulation possibly implicated in detrimental effects of chronic ␤-adrenergic stimulation in end-stage heart failure. We studied the cardiac role of CREM in transgenic mice with heart-directed expression of CREM-Ib⌬C-X, a human cardiac CREM isoform. Transgenic mice displayed atrial enlargement with atrial and ventricular hypertrophy, developed atrial fibrillation, and died prematurely. In vivo hemodynamic assessment revealed increased contractility of transgenic left ventricles probably due to a selective up-regulation of SERCA2, the cardiac Ca 2؉ -ATPase of the sarcoplasmic reticulum. In transgenic ventricles, reduced phosphorylation of phospholamban and of the CREB was associated with increased activity of serine-threonine protein phosphatase 1. The density of ␤ 1 -adrenoreceptor was increased, and messenger RNAs encoding transcription factor dHAND and small G-protein RhoB were decreased in transgenic hearts as compared with wild-type controls. Our results indicate that heart-directed expression of CREM-Ib⌬C-X leads to complex cardiac alterations, suggesting CREM as a central regulator of cardiac morphology, function, and gene expression.The transcriptional activation mediated by the cAMP-response element (CRE) 1 and transcription factors of the CREbinding protein (CREB)/CRE modulator (CREM) family represents an important mechanism of cAMP-responsive gene control (1). CREB and CREM bind as homo-or heterodimers to the CRE, a palindromic consensus element in gene promoters of numerous target genes. One mechanism of CRE-mediated transcriptional activation is the cAMP-dependent protein kinase A (PKA)-dependent phosphorylation of a critical serine in activating isoforms of CREB or CREM, finally leading to activation of the transcriptional complex (2). Inhibitory CREM or CREB isoforms lack functional domains that mediate transcriptional activation or regulation by phosphorylation. Those repressors bind to the CRE as homodimers or as heterodimers in combination with other activating or inhibitory isoforms and suppress transcriptional activation by displacing functionally active dimers from the CRE.Several studies suggested that CRE-mediated transcriptional regulation plays an important role in cardiac gene regulation contributing to the pathophysiology of heart failure: (i) CREB and CREM are both expressed in human heart (3, 4); (ii) transgenic mice with heart-directed expression of a nonphosphorylatable, dominant-negative CREB isoform (dnCREB) (5) or of ATF3 (6), another repressor of CRE-mediated transcriptional activation, developed cardiac hypertrophy and signs of heart failure; and (iii) CREM-deficient mice (general knockout) displayed left ventricular dysfunction in the absence of hypertrophy and premature death (7,8).Here, we tested the role of CREM-Ib⌬C-X, a CREM isoform previously isolated from ...

Congestive heart failure is the common endpoint of various cardiac diseases representing a leading cause of cardiovascular mortality in Western countries. Characteristic functional alterations of the failing heart are explained by expressional changes of myocardial regulatory proteins; however, little is known about underlying mechanisms regulating cardiac gene expression in the failing heart. Here, we address the specific role of transcription factor CREM for cardiac function in CREM mutant mice with complete inactivation of the CREM gene. We show that CREM mutant mice display distinct alterations of cardiac function resembling characteristic functional defects of the failing heart. Left ventricular hemodynamic assessment of CREM mutant mice revealed impairment of both cardiac contraction and relaxation in basal state, as well as a decreased responsiveness to beta-adrenergic stimulation. The diminished cardiac contractile performance was associated with a selective down-regulation of beta1-adrenergic receptors and a decreased ventricular expression of SERCA, the Ca2+-ATPase of the sarcoplasmic reticulum. The cardiac phenotype of CREM mutant mice provides the first evidence that CREM represents an important key regulator of cardiac gene expression, which is essential for normal left ventricular contractile performance and response to beta-adrenoreceptor stimulation.

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