Transcription enhancer factor-1-related factor-transgenic mice develop cardiac conduction defects associated with altered connexin phosphorylation
Transcription enhancer factor-1-related factor-transgenic mice develop cardiac conduction defects associated with altered connexin phosphorylation
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DOI：
10.1161/01.cir.0000146902.84099.26
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发表时间：
2004-11-09
期刊：
影响因子：
37.8
通讯作者：
Stewart, AFR
中科院分区：
文献类型：
--
作者：
Chen, HH;Baty, CJ;Stewart, AFR
背景：传导系统缺陷和心室传导减慢在收缩功能障碍患者中很常见，可导致心律失常和猝死。在心力衰竭的动物模型中，心脏α(1)-肾上腺素能信号被组成性激活。在这里，我们报告了α(1)-肾上腺素能信号的组成激活对连接蛋白磷酸化和心脏传导的影响。方法与结果：制备了心肌细胞中介导α(1)-肾上腺素能信号通路的转录因子RTEF-1（转录增强因子-1相关因子）心脏特异性过表达的转基因小鼠。表面和心内心电图显示RTEF-1小鼠PR、QRS和AH间期延长，出现进行性心房心律失常。使用电压敏感染料的光学成像显示心房和心室心肌传导速度较慢。RTEF-1转基因心肌细胞之间的细胞间染料转移证实了细胞水平上的传导受损。传导缺陷与connexin40和connexin43的去磷酸化和蛋白磷酸酶1 β (pp1 β)的上调有关。pp1 β在HeLa细胞中的过度表达使心脏连接蛋白去磷酸化。共聚焦显微镜显示，RTEF-1小鼠心脏间隙连接中去磷酸化的连接蛋白43水平增加，这表明传导缺陷是由间隙连接传导受损而非组装造成的。结论：通过RTEF-1转录因子组成性激活α(1)-肾上腺素能信号通路可导致pp1 β表达的慢性升高和连接蛋白的去磷酸化。这一机制可能是心脏传导缺陷的基础。
Background-Conduction system defects and slowed ventricular conduction are common in patients with systolic dysfunction and contribute to arrhythmias and sudden death. In animal models of heart failure, cardiac alpha(1)-adrenergic signaling is constitutively activated. Here, we report the effects of constitutive activation of alpha(1)-adrenergic signaling on connexin phosphorylation and cardiac conduction.Methods and Results-Transgenic mice were generated with cardiac-specific overexpression of the transcription factor RTEF-1 (transcription enhancer factor-1-related factor), which mediates alpha(1)-adrenergic signaling in cardiac myocytes. Surface and intracardiac ECGs revealed prolongation of the PR, QRS, and AH intervals and the appearance of progressive atrial arrhythmias in RTEF-1 mice. Optical mapping using voltage-sensitive dye revealed slower conduction velocities across the atrial and ventricular myocardium. Intercellular dye transfer between RTEF-1 transgenic cardiac myocytes confirmed impaired conduction at the cellular level. Conduction defects were correlated with dephosphorylation of connexin40 and connexin43 and upregulation of protein phosphatase 1beta (PP1beta). Overexpression of PP1beta in HeLa cells dephosphorylated cardiac connexin. Confocal microscopy revealed increased levels of dephosphorylated connexin43 at the cardiac gap junctions in RTEF-1 mice, suggesting that defective conduction is a result of impaired gap-junction conductance rather than assembly. Conclusion-Constitutive activation of alpha(1)-adrenergic signaling through the RTEF-1 transcription factor results in chronic elevation of PP1beta expression and connexin dephosphorylation. This mechanism may underlie some defects in cardiac conduction.