Atrial fibrillation and heart failure-associated remodeling of two-pore-domain potassium (K2P) channels in murine disease models: focus on TASK-1
Atrial fibrillation and heart failure-associated remodeling of two-pore-domain potassium (K2P) channels in murine disease models: focus on TASK-1
复制标题
DOI：
10.1007/s00395-018-0687-9
复制
发表时间：
2018-06
影响因子：
9.5
通讯作者：
F. Wiedmann;J. Schulte;B. Gomes;M. Zafeiriou;Antonius Ratte;Franziska S. Rathjens;E. Fehrmann;B. Scholz;N. Voigt;F. Müller;Dierk Thomas;H. Katus;C. Schmidt
中科院分区：
文献类型：
--
作者：
F. Wiedmann;J. Schulte;B. Gomes;M. Zafeiriou;Antonius Ratte;Franziska S. Rathjens;E. Fehrmann;B. Scholz;N. Voigt;F. Müller;Dierk Thomas;H. Katus;C. Schmidt
了解心房颤动(房颤)时心房组织重构和心律失常发生的分子机制对于开发特定的治疗方法是至关重要的。双孔结构域钾通道(K2P)调节细胞兴奋性，最近发现TASK-1(K2P3.1)电流改变房颤和心力衰竭(HF)的心房动作电位时程。寻找与人类病理生理变化相似的房颤动物模型是一项具有挑战性的任务。本研究旨在分析K2P通道在小鼠心脏中的表达模式，并评估K2P通道在小鼠房颤和心力衰竭模型中的表达调节。用实时定量定量聚合酶链式反应和免疫印迹方法检测了房颤[cAMP反应元件调节剂-IbΔC-X转基因动物]和心功能不全(心功能不全)小鼠模型心肌K2P通道的表达。克隆的小鼠、人和猪TASK-1通道在非洲爪蛙细胞中异源表达。采用双电极电压钳实验进行功能表征。在小鼠模型中，在K2P通道家族成员中，TASK-1在房室组织样本中的表达水平最高。此外，K2P2.1、K2P5.1和K2P6.1均有显著的表达水平。在CREM转基因小鼠中，TASK-1的心房表达与野生型动物相比显著降低。在TAC诱导的压力超负荷的小鼠模型中，心室TASK-1的表达保持不变，而心房TASK-1的水平显著下调。在非洲爪哇卵母细胞中异源表达时，小鼠、猪和人类TASK-1的电流表现出相似的特征。在小鼠中，TASK-1通道显示出强劲的心脏表达。小鼠、猪和人类的TASK-1通道有功能上的相似性。在小鼠房颤和心力衰竭模型中，心房TASK-1表达的失调提示了心律失常发生的机制。
Understanding molecular mechanisms involved in atrial tissue remodeling and arrhythmogenesis in atrial fibrillation (AF) is essential for developing specific therapeutic approaches. Two-pore-domain potassium (K2P) channels modulate cellular excitability, and TASK-1 (K2P3.1) currents were recently shown to alter atrial action potential duration in AF and heart failure (HF). Finding animal models of AF that closely resemble pathophysiological alterations in human is a challenging task. This study aimed to analyze murine cardiac expression patterns of K2Pchannels and to assess modulation of K2Pchannel expression in murine models of AF and HF. Expression of cardiac K2Pchannels was quantified by real-time qPCR and immunoblot in mouse models of AF [cAMP-response element modulator (CREM)-IbΔC-X transgenic animals] or HF (cardiac dysfunction induced by transverse aortic constriction, TAC). Cloned murine, human, and porcine TASK-1 channels were heterologously expressed inXenopus laevisoocytes. Two-electrode voltage clamp experiments were used for functional characterization. In murine models, among members of the K2Pchannel family, TASK-1 expression displayed highest levels in both atrial and ventricular tissue samples. Furthermore, K2P2.1, K2P5.1, and K2P6.1 showed significant expression levels. In CREM-transgenic mice, atrial expression of TASK-1 was significantly reduced in comparison with wild-type animals. In a murine model of TAC-induced pressure overload, ventricular TASK-1 expression remained unchanged, while atrial TASK-1 levels were significantly downregulated. When heterologously expressed inXenopus oocytes, currents of murine, porcine, and human TASK-1 displayed similar characteristics. TASK-1 channels display robust cardiac expression in mice. Murine, porcine, and human TASK-1 channels share functional similarities. Dysregulation of atrial TASK-1 expression in murine AF and HF models suggests a mechanistic contribution to arrhythmogenesis.