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

 
: Lewin, G.; Matus, M.; Basu, A.; Frebel, K.; Rohsbach, S.P.; Safronenko, A.; Seidl, M.D.; Stümpel, F.; Buchwalow, I.; König, S.; Engelhardt, S.; Lohse, M.J.; Schmitz, W.; Müller, F.U.

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Circulation 119 (2009), Nr.1, S.79-88
ISSN: 0009-7322
ISSN: 0069-4193
ISSN: 0065-8499
Englisch
Zeitschriftenaufsatz
Fraunhofer ITEM ()
molecular biology; myocardium; receptor; adrenergic; beta adrenoceptor

Abstract
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.

: http://publica.fraunhofer.de/dokumente/N-89511.html