Grant-in-Aid for Scientific Research (B)
|Allocation Type||Single-year Grants |
|Research Institution||Tokyo Medical and Dental University |
KAWANO Seiko(2004) Tokyo Medical and Dental University, Associate Professor, 難治疾患研究所, 助教授 (00177718)
平岡 昌和(2002-2003) 東京医科歯科大学, 難治疾患研究所, 教授 (80014281)
HIRANO Yuhi Tokyo Medical and Dental University, Associate Professor, 難治疾患研究所, 助教授 (00181181)
NAKAYAKA Hitoshi Kumamoto University, Professor, 大学院・医学薬学研究部, 教授 (70088863)
HIRAOKA Masayasu Tokyo Medical and Dental University, Emeritus Professor, 難治疾患研究所, 教授 (80014281)
KUNIYASU Akihikko Kumamoto University, Associate professor, 大学院・医学薬学研究部, 助教授 (90241348)
川野 誠子 東京医科歯科大学, 難治疾患研究所, 助教授 (00177718)
|Project Period (FY)
2002 – 2004
Completed(Fiscal Year 2004)
|Budget Amount *help
¥14,700,000 (Direct Cost : ¥14,700,000)
Fiscal Year 2004 : ¥4,000,000 (Direct Cost : ¥4,000,000)
Fiscal Year 2003 : ¥5,300,000 (Direct Cost : ¥5,300,000)
Fiscal Year 2002 : ¥5,400,000 (Direct Cost : ¥5,400,000)
|Keywords||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 / 心不全 / 容積感受性クロールチャネル / ペースメーカーチャネル / 圧負荷|
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
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