Lewin, G.G.LewinMatus, M.M.MatusBasu, A.A.BasuFrebel, K.K.FrebelRohsbach, S.P.S.P.RohsbachSafronenko, A.A.SafronenkoSeidl, M.D.M.D.SeidlStümpel, F.F.StümpelBuchwalow, I.I.BuchwalowKönig, S.S.KönigEngelhardt, S.S.EngelhardtLohse, M.J.M.J.LohseSchmitz, W.W.SchmitzMüller, F.U.F.U.Müller2022-03-042022-03-042009https://publica.fraunhofer.de/handle/publica/21808610.1161/CIRCULATIONAHA.108.7865332-s2.0-59049107401Background: 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.enmolecular biologymyocardiumreceptoradrenergicbeta adrenoceptor610616journal article