The molecular mechanisms of remodeling of ion channels leading to arrhtymias in hypertrophy and cardiomyopathy.

心脏疾病，如心脏肥大和心力衰竭，往往提供了致命的心律失常的基础，彻底改变离子电流和离子通道的表达（电生理“重塑”）。我们使用两种不同的动物模型（心肌肥厚和心肌病）来研究重塑的分子机制和导致心律失常的特定条件。（1）腹主动脉缩窄致大鼠心脏肥大时，HCN 2、HCN 4和ClC-3的mRNA水平呈双相变化：早期降低，晚期升高。这些通道的重构可以通过给予血管紧张素II受体阻断剂或Ca^2+通道阻断剂来预防。（2）J-2-N心肌病仓鼠在心力衰竭过程中和发生心力衰竭后，心电图异常，心律失常频繁。电生理研究表明，J-2-N仓鼠的I_2电流密度降低<to>，恢复特性改变 关于我们 失活，尤其是心外膜肌细胞。我们还对几种人类离子通道疾病进行了功能分析，这有助于将离子通道的遗传异常与临床表现联系起来。在LQT 2患者中发现HERG C端区域的移码突变（1122 fs/147）。该突变引起I_电流功能的丧失<Kr>，这是由于失活特性的改变和细胞表面上通道蛋白的表达减少（运输缺陷）。我们还分析了一个新的突变KCNQ 1（Ala 178 fs/105）在LQT 1患者中发现。KCNQ 1突变体形成异源多聚体，并<Ks>以显性负效应抑制电流。这也是由于运输缺陷，如突变蛋白的胞内滞留所证明的。因此，我们的研究阐明了心脏疾病中遇到的血管生成机制的几个方面，其中通道蛋白的重塑或性质改变起着重要作用。少

Heart diseases, such as cardiac hypertrophy and heart failure, often provide basis for lethal arrhythmias thorough alterations in ionic currents and ion channel expressions (electrophysiological "remodeling"). We used two different animal models (hypertrophy and cardiomyopathy) to investigate molecular mechanisms of remodeling and specific conditions leading to arrhythmias.(1)When rat hearts were hypertrophied through the banding of abdominal aorta, mRNA levels of HCN2, HCN4, and ClC-3 showed biphasic changes : decrease in the early phase and increase in the late phase. Remodeling of these channels could be prevented through the administration of either an angiotensin II receptor blocker or a Ca^<2+> channel blocker.(2)J-2-N cardiomyopathic hamsters show abnormal ECG findings and frequent arrhythmias during and after the development of cardiac failure. Electrophysiological studies disclosed that J-2-N hamsters have decreased current density of I_<to> with altered properties of recovery … More from inactivation, especially in epicardial myocytes. These variations produced rate-dependent abnormalities in APDs, often associated with arrhythmias.We also performed functional analysis of several human ion channel diseases, which helped to link the genetic abnormalities of ion channels with clinical manifestations.A frameshift mutation at the C-terminus region of HERG (1122fs/147) was identified in a LQT2 patient. This mutation evoked a loss of function of the I_<Kr> current, due to changes in inactivation properties and reduced expression of the channel protein on the cell surface (trafficking defect). We also analyzed a novel mutation of KCNQ1 (Ala178fs/105) identified in a LQT1 patient. This KCNQ1 mutant formed hetero-multimer and caused a suppression of I_<Ks> current as a dominant-negative effect. This was also due to the trafficking defect, as proved by an intracellular retention of the mutant protein.Our study thus clarified several aspects of the mechanisms of arrhythmogenesis encountered in heart diseases, where remodeling or altered properties of the channel proteins played important roles. Less