2004 Fiscal Year Final Research Report Summary
The molecular mechanisms of remodeling of ion channels leading to arrhtymias in hypertrophy and cardiomyopathy.
| Project/Area Number |
14370404
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Thoracic surgery
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
KAWANO Seiko Tokyo Medical and Dental University, Associate Professor, 難治疾患研究所, 助教授 (00177718)
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| Co-Investigator(Kenkyū-buntansha) |
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)
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| Project Period (FY) |
2002 – 2004
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| Keywords | Ion Channel / Arrhythmia / HERG Channel / Ca Channel / K Channel / Cardiomyopathic hamster / Lethal Arrhtymia / Remodeling / Heart Failure |
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| Research Abstract |
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
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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
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Research Products
(30 results)
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[Journal Article] Novel C-terminus frameshift mutation, 1122fs/147, of HERG in LQT2 : additional amino acids generated by frameshift cause accelerated inactivation.2004
Author(s)
T.Sasano, K.Ueda, M Orikabe, Y.Hirano, S.Kawano, M.Yasunami, M.Isobe, A.Kimura, M.Hiraoka
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Journal Title
J.Mol.Cell.Cardiol. 37
Pages: 1205-1211
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Truncated KCNQ1. mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking defect.2004
Author(s)
Y.Aizawa, K.Ueda, L.Wua, N.Inagaki, T.Hayashi, M.Takahashi, M.Ohta, S.Kawano, Y.Hirano, M.Yasunamic, Y.Aizawa, A.Kimura, M.Hiraoka
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Journal Title
FEBS Letters 574
Pages: 145-150
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking defect.2004
Author(s)
Y.Aizawa, K.Ueda, L.Wua, N.Inagaki, T.Hayashi, M.Takahashi, M.Ohta, S.Kawano, Y.Hirano, M.Yasunamic, Y.Aizawa, A.Kimura, M.Hiraoka
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Journal Title
FEBS Letters 574
Pages: 145-150
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.2004
Author(s)
Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, Higashiuesato Y, Hirano, Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori M, Hiraoka M, Kimura A.
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Journal Title
J.Biol.Chem. 279
Pages: 27194-27198
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Electrical connections between pulmonary veins. Implications for ostial ablation of pulmonary veins in patients with paroxyxmal atrial fibrillation.2002
Author(s)
Takahashi A, Iesaka Y, Takahashi Y, Takahashi R, Kobayashi K, Takagi K, Kuboyama O, Nishimori T, Takei H, Amemiya H, Fujiwara H, Hiraoka M.
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Journal Title
Circulation 105
Pages: 2998-3003
Description
「研究成果報告書概要(和文)」より
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