抄録
In the early stages of cardiac development, HCN4 is expressed in ventricle as well as pacemaker region. The expression of HCN4 is restricted to pacemaker region during development. In hypertrophied adult heart, however, HCN4 is re-expressed in the ventricle. We explored the transcriptional mechanisms of HCN4 gene using luciferase reporter assay. The promoter deletion analysis showed that proximal -847 bps fragment acted as a minimal promoter, whose activity was significantly higher in embryonic than in neonatal myocyte. The minimal promoter activity was insensitive to pharmacological hypertrophic stimuli. The second intron of hcn4 possesses NRSE, a cis-acting element of neuron-restrictive silencing factor (NRSF). When ∼3 kb fragment containing NRSE was fused to the minimal promoter, transcriptional activity was repressed in neonatal myocytes, which was reversed by hypertrophic stimulation. NRSF mediated repression was significantly weaker in fetal myocytes.In accordance with this, HCN4 was re-expressed in the ventricle of transgenic mice expressing dominant negative NRSF in the heart (dnNRSF Tg). dnNRSF Tg exhibited dilated cardiomyopathy and susceptibility to lethal ventricular arrhythmia. In the ventricular myocytes of dnNRSF Tg, the resting membrane potential was more depolarized, and the action potential duration was longer than wild type. Early after depolarization was consistently induced in the presence of isoprotenol in dnNRSF Tg. These electrophysiological remodeling may be responsible for the lethal arrhythmia. [Jpn J Physiol 55 Suppl:S45 (2005)]
