Impaired cardiac contraction and relaxation and decreased expression of sarcoplasmic Ca2+-ATPase in mice lacking the CREM gene
Impaired cardiac contraction and relaxation and decreased expression of sarcoplasmic Ca2+-ATPase in mice lacking the CREM gene
复制标题
DOI：
10.1096/fj.02-0486fje
复制
发表时间：
2002-11-01
期刊：
影响因子：
4.8
通讯作者：
Schmitz, W
中科院分区：
文献类型：
--
作者：
Müller, FU;Lewin, G;Schmitz, W
充血性心力衰竭是各种心脏病的共同终点，是西方国家心血管死亡的主要原因。心脏衰竭的特征性功能改变可以通过心肌调节蛋白的表达变化来解释；然而，人们对衰竭心脏中调节心脏基因表达的潜在机制知之甚少。在这里，我们探讨了转录因子 CREM 对 CREM 基因完全失活的 CREM 突变小鼠心脏功能的特定作用。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，基础状态下心脏收缩和舒张均受损，并且对 β-肾上腺素能刺激的反应性降低。心脏收缩性能的减弱与β(1)-肾上腺素能受体的选择性下调和SERCA（肌浆网的Ca2+-ATP酶）心室表达的减少有关。 CREM 突变小鼠的心脏表型提供了第一个证据，证明 CREM 代表心脏基因表达的重要关键调节因子，这对于正常的左心室收缩性能和对 β-肾上腺素受体刺激的反应至关重要。
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 beta(1)-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.