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

离子通道重塑导致肥厚和心肌病心律失常的分子机制。

• 批准号: 14370404
• 负责人: KAWANO Seiko
• 金额: $ 9.41万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370404/
• 关键词: Ion Channel; Arrhythmia; HERG Channel; Ca Channel; K Channel; Cardiomyopathic hamster; Lethal Arrhtymia; Remodeling; Heart Failure; HERG; KCNQ1; Long QT症候群; チャネル輸送; チャネルリモデリング; 一過性外向きKチャネル; L型Caチャネル; 蛋白チロシン燐酸化; チャネル蛋白発現; HERG電流密度減少; 心肥大

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

心脏疾病，如心肌肥大和心力衰竭，通常为致命性心律失常提供基础，通过离子电流和离子通道表达的改变(电生理“重构”)。我们使用两种不同的动物模型(肥厚和心肌病)来研究心脏重构的分子机制和导致心律失常的特定条件：(1)当通过腹主动脉缩窄造成大鼠心脏肥厚时，HCN_2、HCN_4和ClC-3的mRNA表达呈现早期降低和晚期升高的双相变化。这些通道的重塑可以通过给予血管紧张素II受体阻滞剂或钙通道阻滞剂来防止。(2)J-2-N心肌病仓鼠在心力衰竭发展过程中和之后表现出异常的心电图和频繁的心律失常。电生理研究表明，J-2-N仓鼠的恢复…特性发生改变，其电流密度降低更多的是由于失活，特别是在心外膜肌细胞。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。在一名LQT2患者中发现了HERG C末端区域的移码突变(1122fs/147)。由于失活特性的改变和细胞表面通道蛋白表达的减少(运输缺陷)，这种突变引起了I_&lt；Kr&gt；电流功能的丧失。我们还分析了在一例LQT1患者中发现的KCNQ1的一个新突变(Ala178fs/105)。该KCNQ1突变体形成异源多聚体，并以显性负效应抑制I_(lt；Ks&gt)电流。这也是由于转运缺陷，突变蛋白在细胞内的滞留证明了这一点。因此，我们的研究阐明了心脏疾病中遇到的心律失常发生机制的几个方面，其中通道蛋白的重塑或性质改变发挥了重要作用。较少

项目成果

Regional and frequency-dependent changes in action potentials and transient outward K^+ currents in ventricular myocytes from J-2-K cardiomyopathic hamsters.

J-2-K 心肌病仓鼠心室肌细胞动作电位和瞬时外向 K^ 电流的区域和频率依赖性变化。

• 发表时间: 2003
• 期刊: Basic Res Cardiol 98
• 作者: Kocic I;Hirano Y;Kawano S;Hiraoka M.
• 通讯作者: Hiraoka M.

Electrical connection between left superior and inferior pulmonary veins in a patient with paroxysmal atrial fibrillation.

阵发性心房颤动患者左上肺静脉和下肺静脉之间的电连接。

• 发表时间: 2002
• 期刊: J Cardiovasc Electrophysiol 13
• 作者: Takahashi Y;Iesaka Y;Takahashi A;Hiraoka M.
• 通讯作者: Hiraoka M.

Electrical connections between pulmonary veins. Implications for ostial ablation of pulmonary veins in patients with paroxyxmal atrial fibrillation.

肺静脉之间的电连接。

• 发表时间: 2002
• 期刊: Circulation 105
• 作者: Takahashi A;Iesaka Y;Takahashi Y;Takahashi R;Kobayashi K;Takagi K;Kuboyama O;Nishimori T;Takei H;Amemiya H;Fujiwara H;Hiraoka M.
• 通讯作者: Hiraoka M.

Wu L-M, Orikabe M, Hirano Y, Kawano S, Hiraoka M.: "Effects of Na^+ channel blocker, pilsicainide, on HERG current expressed in HEK-293 cells."J Cardiovasc Pharmacol. 42. 410-418 (2003)

Wu L-M、Orikabe M、Hirano Y、Kawano S、Hiraoka M.：“Na + 通道阻滞剂、匹西卡尼对 HEK-293 细胞中表达的 HERG 电流的影响。”J Cardiovasc Pharmacol。

Hiramatsu, M.: "Ion channel remodeling in cardiac hypertrophy is prevented by blood pressure lowering without affecting"heart weight increase in rats with abdominal aortic banding.j. Cardiovasc. Pharmacol. 39. 866-874 (2002)

Hiramatsu, M.：“通过降低血压可以防止心脏肥大中的离子通道重塑，而不影响”腹主动脉结扎大鼠的心脏重量增加。