抄録
It is well known that fetal types of cardiac ion channels, i.e. hyperpolarization activated cation channel (Ih) and T-type Ca2+ channel (ICa-T) are re-expressed in ventricular myocytes of hypertrophied heart, giving rise to electrophysiological remodeling. We have recently reported that a transcriptional repressor, neuron restricted silencing factor (NRSF) regulated the expression of fetal cardiac genes such as atrial naturetic factor. Transgenic mice expressing dominant negative NRSF in their heart (dnNRSF Tg), exhibited dilated cardiomyopathy and susceptibility to lethal ventricular arrhythmia. In the present study, we explored the mechanism of lethal arrhythmia in dnNRSF Tg. Among genes encoding Ih and ICa-T, hcn2, hcn4 and cacna1h possess NRSE, a cis-acting element of NRSF. In the ventricle of dnNRSF Tg, mRNAs of HCN2, HCN4 and CACNA1H were re-expressed. In accordance with this, Ih was activated only in the cardiac myocyte of dnNRSF Tg, but not in wild type littermate (WT). The density of ICa-T was higher in dnNRSF Tg than in WT. ICa-T in dnNRSF Tg was almost completely suppressed by, whereas ICa-T in WT was insensitive to, 50 μM Ni2+. The resting membrane potential was more depolarized, and the action potential duration was prolonged in dnNRSF Tg. Early after depolarization was consistently induced in dnNRSF Tg in the presence of 1 μM isoprotenol. These electrophysiological alterations appeared responsible for the lethal arrhythmia in dnNRSF Tg mice. [Jpn J Physiol 54 Suppl:S107 (2004)]
