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A new approach to prevent life-threatening arrhythmias by gene transfer of a dominant negative mutant of thyroid horm6ne receptors.

通过甲状腺激素受体显性失活突变体的基因转移来预防危及生命的心律失常的新方法。

基本信息

批准号：
12670657
负责人：
LEE Jong-kook
金额：
$ 2.24万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

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.

背景资料。胺碘酮强大的抗心律失常作用部分归因于通过与甲状腺激素的拮抗而诱导心脏选择性甲状腺功能减退。如果是这样的话，可以通过抑制核甲状腺激素受体(TR)功能来模拟药物作用。用携带显性负性tr突变体(AdTRG345R)的重组腺病毒通过导管技术感染培养的大鼠心肌细胞和大鼠心脏。感染后用甲状腺素治疗10天，形成全身性甲状腺功能亢进症。AdTRG345R感染心肌细胞后，1 Hz动作电位时程延长38%，瞬时外向钾电流密度降低54%，持续外向钾电流降低42%(n=8~15，p9&lt；0.05)。大鼠心脏感染AdTRG345R后，心电图RR延长18%，QT延长22%(n=8，p&lt；0.01)。腺病毒介导的野生型受体在心肌细胞和心脏中都引起了相反的变化。程序刺激诱发8/8(100%)对照组大鼠持续性室性心动过速(VT)，但仅2/8(25%)AdTRG345R感染大鼠诱发持续性室性心动过速。在AdTRG345R感染的大鼠心脏诱发的室性心动过速明显长于对照组大鼠，持续时间明显短于对照组。结论。体外和体内转基因AdTRG345R均可产生大鼠心脏甲状腺功能减退的电生理特征。因此，基因组诱导心脏选择性甲状腺功能减退症是一种潜在的有用的新的抗心律失常方法。