Transgenic overexpression of the Ca2+-binding protein S100A1 in the heart leads to increased in vivo myocardial contractile performance
Transgenic overexpression of the Ca2+-binding protein S100A1 in the heart leads to increased in vivo myocardial contractile performance
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DOI：
10.1074/jbc.m301788200
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发表时间：
2003-09-05
影响因子：
4.8
通讯作者：
Koch, WJ
中科院分区：
文献类型：
--
作者：
Most, P;Remppis, A;Koch, WJ
S100A1是EF-Hand家族的一种钙离子敏感蛋白，在心肌组织中表达最高，体外研究表明，心脏S100A1的过度表达可以增强心肌细胞的收缩特性。为了研究S100A1在体内的生理后果，我们建立了心脏限制性过表达S100A1的转基因小鼠。对两个独立的转基因小鼠品系进行的鉴定表明，S100A1在心肌中的4倍过度表达显示，体内基础心功能显着增强，在β-肾上腺素能受体刺激后仍保持升高。从S100A1转基因小鼠分离的心室肌细胞的收缩功能和对钙的处理能力都增加了。S100A1促进细胞内钙循环与肌浆网钙含量增加和肌浆网钙离子诱导的钙释放增加有关，S100A1与心肌兰尼定受体有关。β-肾上腺素能信号转导和主要的心肌钙循环蛋白未见改变，慢性心脏S100A1过表达也未见肥厚迹象。我们的发现表明，S100A1在体内可能通过与兰尼定受体相互作用而在心脏功能调节中发挥重要作用。由于S100A1蛋白在心力衰竭中的表达下调，增加心脏中S100A1的表达可能是一种增强收缩能力的新手段。
S100A1, a Ca2+-sensing protein of the EF-hand family, is most highly expressed in myocardial tissue, and cardiac S100A1 overexpression in vitro has been shown to enhance myocyte contractile properties. To study the physiological consequences of S100A1 in vivo, transgenic mice were developed with cardiac-restricted overexpression of S100A1. Characterization of two independent transgenic mouse lines with similar to4-fold overexpression of S100A1 in the myocardium revealed a marked augmentation of in vivo basal cardiac function that remained elevated after beta-adrenergic receptor stimulation. Contractile function and Ca2+ handling properties were increased in ventricular cardiomyocytes isolated from S100A1 transgenic mice. Enhanced cellular Ca2+ cycling by S100A1 was associated both with increased sarcoplasmic reticulum Ca2+ content and enhanced sarcoplasmic reticulum Ca2+-induced Ca2+ release, and S100A1 was shown to associate with the cardiac ryanodine receptor. No alterations in beta-adrenergic signal transduction or major cardiac Ca2+-cycling proteins occurred, and there were no signs of hypertrophy with chronic cardiac S100A1 overexpression. Our findings suggest that S100A1 plays an important in vivo role in the regulation of cardiac function perhaps through interacting with the ryanodine receptor. Because S100A1 protein expression is downregulated in heart failure, increasing S100A1 expression in the heart may represent a novel means to augment contractility.