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Heart-directed expression of a human cardiac isoform of cAMP-response element modulator in transgenic mice.

Authors: Muller, FU  Lewin, G  Baba, HA  Boknik, P  Fabritz, L  Kirchhefer, U  Kirchhof, P  Loser, K  Matus, M  Neumann, J  Riemann, B  Schmitz, W 
Citation: Muller FU, etal., J Biol Chem. 2005 Feb 25;280(8):6906-14. Epub 2004 Nov 29.
Pubmed: (View Article at PubMed) PMID:15569686
DOI: Full-text: DOI:10.1074/jbc.M407864200

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 beta-adrenergic stimulation in end-stage heart failure. We studied the cardiac role of CREM in transgenic mice with heart-directed expression of CREM-IbDeltaC-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 beta(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-IbDeltaC-X leads to complex cardiac alterations, suggesting CREM as a central regulator of cardiac morphology, function, and gene expression.

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CRRD Object Information
CRRD ID: 1581291
Created: 2006-09-25
Species: All species
Last Modified: 2006-09-25
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.