Müller Frank U, Lewin Geertje, Baba Hideo A, Bokník Peter, Fabritz Larissa, Kirchhefer Uwe, Kirchhof Paulus, Loser Karin, Matus Marek, Neumann Joachim, Riemann Burkhard, Schmitz Wilhelm
Institute of Pharmacology and Toxicology, University of Münster, Domagkstrasse 12, D-48149 Münster, Germany.
J Biol Chem. 2005 Feb 25;280(8):6906-14. doi: 10.1074/jbc.M407864200. Epub 2004 Nov 29.
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.
由环磷酸腺苷反应元件（CRE）介导的转录激活以及CRE结合蛋白（CREB）/CRE调节剂（CREM）家族的转录因子，代表了一种环磷酸腺苷依赖性基因调控的重要机制，这可能与终末期心力衰竭中慢性β-肾上腺素能刺激的有害作用有关。我们研究了CREM在心脏定向表达人心脏CREM亚型CREM-IbDeltaC-X的转基因小鼠中的心脏作用。转基因小鼠表现出心房扩大以及心房和心室肥大，发生心房颤动，并过早死亡。体内血流动力学评估显示转基因左心室的收缩力增加，这可能是由于肌浆网的心脏钙（2+）-ATP酶SERCA2的选择性上调所致。在转基因心室中，受磷蛋白和CREB的磷酸化减少与丝氨酸-苏氨酸蛋白磷酸酶1的活性增加有关。与野生型对照相比，转基因心脏中β（1）-肾上腺素能受体的密度增加，而编码转录因子dHAND和小G蛋白RhoB的信使核糖核酸减少。我们的结果表明，心脏定向表达CREM-IbDeltaC-X会导致复杂的心脏改变,表明CREM作为心脏形态、功能和基因表达的核心调节因子。
