A new approach to prevent life-threatening arrhythmias by gene transfer of a dominant negative mutant of thyroid horm6ne receptors.
| Project/Area Number |
12670657
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Nagoya University |
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Principal Investigator |
LEE Jong-kook Nagoya Univ., Res. Inst. Of Environ. Med., Assistant Professor, 環境医学研究所, 助手 (60303608)
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| Co-Investigator(Kenkyū-buntansha) |
SEO Hisao Nagoya Univ., Res. Inst. Of Environ. Med., Professor, 環境医学研究所, 教授 (40135380)
KODAMA Itsuo Nagoya Univ., Res. Inst. Of Environ. Med., Professor, 環境医学研究所, 教授 (30124720)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Keywords | lethal ventricular arrhythmias / gene therapy / thyroid hormone recptors / adenovirus / 遺伝子導入 / 心臓電気生理 / パッチクランプ / 活動電位持続時間 / 一過性外向きK^+電流 / 心電図 |
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| Research Abstract |
Background. Potent antiarrhythmic effects of amiodarone have been attributed, in part, to induction of cardio-selective hypothyroidism through antagonism with thyroid hormone. If it is the case, the drug action can be mimicked by inhibition of nuclear thyroid hormone receptor (TR) function.Methods and Results. A recombinant adenovirus carrying a dominant negative TR mutant (AdTRG345R) was used to infect cultured rat ventricular myocytes, and rat hearts with a catheter-based technique. After infection, the rats were treated with thyroxine for 10 days to produce systemic hyperthyroidism. Infection of myocytes with AdTRG345R resulted in a prolongation of action potential duration at 1 Hz by 38%, reduction of the transient outward K^+ current density by 54% and sustained outward K^+ current by 42% compared to control rats infected with adenovirus vector alone (n=8-15,p9<0.05). Infection of rat hearts with AdTRG345R resulted in prolongation of RR and QT by 18% and 22%, respectively, on electrocardiogram compared with control (n=8, p<0.01). Adenovirus-mediated delivery of wild-type TR caused opposite changes both in myocytes and heart. Sustained ventricular tachycardia (VT) was induced by programmed stimulation in 8/8 (100%) control rats, but only in 2/8 (25%) AdTRG345R-infected rats. VTs induced in the AdTRG345R-infected hearts had significantly longer cycle length and shorter duration than VTs in control rats. Conclusions. Hypothyroid-like electrophysiological features of rat heart could be produced by in vitro and in vivo gene transfer of AdTRG345R. It is thus uggested that genomic induction of cardio-selective hypothyroidism is a potentially useful and novel antiarrhythmic approach.
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Report
(3 results)
Research Products
(10 results)
