Pthophysiological significance of target genes of NRSF, a new transcriptional suppressor, in congestive heart failure

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Aldosterone, one of key molecules which are involved in pathogenesis in heart failure, is synthesized by a specific synthase, CYP11B2, and its gene expression is regulated Ca influx into via T-type calcium channel, Cav 3.2, in adrenal cortical cells. However, the molecular mechanism for aldosterone synthesis in heart failure is not fully understood.Recently we reported that Neuron restrictive silencer factor (NRSF), which binds to neuron restrictive silencer element (NRSE) to suppress transcription of NRSE-containing genes, is involved in the re-induction of a number of cardiac embryonic genes in vitro and in vivo. Mice over-expressing dominant negative NRSF show dilated cardiomyopathy-like cardiac phenotypic changes and sudden cardiac death due to fatal ventricular arrhythmia.We also identified the sequence highly homologous to NRSE sequence is located in transcriptional regulatory region of the CYP11B2 gene and CACNA1H gene, the latter of which encodes subunit of Cav3.2.Here we examined the roles of the NRSE/NRSF system in aldosterone synthesis in human adrenocortical (H295R) cells. Inhibiting endogenous NRSF function by adenovirus vector containing dominant-negative NRSF (AD/dnNRSF) markedly increased aldosterone secretion and CYP11B2 mRNA. AD/dnNRSF also increased levels of CACNA1H mRNA. Efonidipine, dual T/L-type calcium channel blocker, inhibited dnNRSF-induced CYP11B2 mRNA expression and CYP11B2 reporter gene activity from constructs containing a mutated or missing NRSE sequence. Moreover, AD/dnNRSF attenuated AngII- and K^+-induced increases in CYP11B2 mRNA levels.The present findings suggest the NRSE/NRSF system controls aldosterone synthesis in the adrenal gland, which is one of extracardiac compensatory mechanism in heart failure.