Wnt-1 regulation of connexin43 in cardiac myocytes
Wnt-1 regulation of connexin43 in cardiac myocytes
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DOI：
10.1172/jci7798
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发表时间：
2000-01-01
影响因子：
15.9
通讯作者：
Fishman, GI
中科院分区：
文献类型：
--
作者：
Ai, ZW;Fischer, A;Fishman, GI
缝隙连接蛋白43（Cx43）是心脏正常形成和功能的重要组成部分。我们研究了Wnt家族分泌的多肽作为Cx43表达和间隙连接通道功能在分离的心肌细胞和完整心脏中的调节剂的潜在作用。新生大鼠心肌细胞响应于Li+，其模拟Wnt信号，通过积累效应蛋白β-连环蛋白和诱导Cx43 mRNA和蛋白显着。在与Rat-2成纤维细胞或N2 A神经母细胞瘤细胞共培养的心肌细胞中也观察到Cx43表达的诱导，所述细胞被编程为分泌生物活性Wnt-1。通过将Cx43启动子-报告基因构建体转染到心肌细胞中，我们证明了Wnt信号的诱导作用是转录介导的。Cx43的表达增强增加心肌细胞的细胞耦合，荧光黄染料转移和钙波传播。相反，在表现出室性心律失常和间隙连接重构的转基因心肌病小鼠模型中，β-连环蛋白和Cx43表达一致下调。响应Wnt信号，积聚的Cx43与β-catenin共定位在连接膜中;此外，心肌细胞中Cx43的强制表达降低了β-catenin的反式激活潜力。这些发现表明，Wnt信号是心脏中Cx43依赖性细胞间偶联的重要调节剂，并且它们支持信号失调导致肌病心脏中脉冲传播和心律失常改变的假设。
Gap junction channels composed of connexin43 (Cx43) are essential for normal heart formation and function. We studied the potential role of the Wnt family of secreted polypeptides as regulators of Cx43 expression and gap junction channel function in dissociated myocytes and intact hearts. Neonatal rat cardiomyocytes responded to Li+, which mimics Wnt signaling, by accumulating the effector protein beta-catenin and by inducing Cx43 mRNA and protein markedly. Induction of Cx43 expression was also observed in cardiomyocytes cocultured with Rat-2 fibroblasts or N2A neuroblastoma cells programmed to secrete bioactive Wnt-1. By transfecting a Cx43 promoter-reporter gene construct into cardiomyocytes, we demonstrated that the inductive effect of Wnt signaling was transcriptionally mediated. Enhanced expression of Cx43 increased cardiomyocyte cell coupling, as determined by Lucifer Yellow dye transfer and by calcium wave propagation. Conversely in a transgenic cardiomyopathic mouse model that exhibits ventricular arrhythmias and gap junctional remodeling, beta-catenin and Cx43 expression were downregulated concordantly. In response to Wnt signaling, the accumulating Cx43 colocalized with beta-catenin in the junctional membrane; moreover, forced expression of Cx43 in cardiomyocytes reduced the transactivation potential of beta-catenin. These findings demonstrate that Wnt signaling is an important modulator of Cx43-dependent intercellular coupling in the heart, and they support the hypothesis that dysregulated signaling contributes to altered impulse propagation and arrhythmia in the myopathic heart.