Müller Frank U, Lewin Geertje, Matus Marek, Neumann Joachim, Riemann Burkhard, Wistuba Joachim, Schütz Günther, Schmitz Wilhelm
Institute of Pharmacology and Toxicology, University of Münster, Germany.
FASEB J. 2003 Jan;17(1):103-5. doi: 10.1096/fj.02-0486fje. Epub 2002 Nov 15.
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.
充血性心力衰竭是各种心脏疾病的常见终点，是西方国家心血管疾病死亡的主要原因。衰竭心脏的特征性功能改变可通过心肌调节蛋白的表达变化来解释；然而，关于衰竭心脏中调节心脏基因表达的潜在机制却知之甚少。在此，我们研究了转录因子CREM在CREM基因完全失活的突变小鼠心脏功能中的具体作用。我们发现，CREM突变小鼠表现出明显的心脏功能改变，类似于衰竭心脏的特征性功能缺陷。对CREM突变小鼠的左心室血流动力学评估显示，其在基础状态下心脏收缩和舒张功能均受损，对β-肾上腺素能刺激的反应性也降低。心脏收缩性能的减弱与β1-肾上腺素能受体的选择性下调以及肌浆网Ca2+-ATP酶SERCA的心室表达减少有关。CREM突变小鼠的心脏表型首次证明，CREM是心脏基因表达的重要关键调节因子，对正常左心室收缩性能和对β-肾上腺素能受体刺激的反应至关重要。
