PMID- 17011572 OWN - NLM STAT- MEDLINE DCOM- 20070131 LR - 20141120 IS - 0022-2828 (Print) IS - 0022-2828 (Linking) VI - 41 IP - 6 DP - 2006 Dec TI - Class II HDACs mediate CaMK-dependent signaling to NRSF in ventricular myocytes. PG - 1010-22 AB - We recently reported that a transcriptional repressor, neuron-restrictive silencer factor (NRSF), represses expression of fetal cardiac genes, including atrial and brain natriuretic peptide (ANP and BNP), by recruiting class I histone deacetylase (HDAC) and that attenuation of NRSF-mediated repression contributes to the reactivation of fetal gene expression during cardiac hypertrophy. The molecular mechanism by which the activity of the NRSF-HDAC complex is inhibited in cardiac hypertrophy remains unresolved, however. In the present study, we show that class II HDACs (HDAC4 and 5), which are Ca/calmodulin-dependent kinase (CaMK)-responsive repressors of hypertrophic signaling, associate with NRSF and participate in NRSF-mediated repression. Blockade of the CaMK-class II HDAC signaling pathway using a CaMK-resistant HDAC5 mutant, a CaMK inhibitor (KN62) or a dominant-negative CaMK mutant inhibited ET-1-inducible ANP and BNP promoter activity, but that inhibitory effect was abolished by mutation of the neuron-restrictive silencer element (NRSE) within the ANP and BNP promoter. In addition, adenovirus-mediated expression of a dominant-negative NRSF mutant abolished the inhibitory effect of KN62 on ET-1-inducible endogenous ANP gene expression in ventricular myocytes. Finally, the interaction between NRSF and class II HDACs was decreased in both in vitro and in vivo models of cardiac hypertrophy. These findings show that ET-1-induced CaMK signaling disrupts class II HDAC-NRSF repressor complexes, thereby enabling activation of ANP and BNP gene transcription in ventricular myocytes, and shed light on a novel mechanism by which the fetal cardiac gene program is reactivated. FAU - Nakagawa, Yasuaki AU - Nakagawa Y AD - Department of Medicine and Clinical Science, Kyoto Graduate School of Medicine, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto-city, Kyoto 606-8507, Japan. FAU - Kuwahara, Koichiro AU - Kuwahara K FAU - Harada, Masaki AU - Harada M FAU - Takahashi, Nobuki AU - Takahashi N FAU - Yasuno, Shinji AU - Yasuno S FAU - Adachi, Yuichiro AU - Adachi Y FAU - Kawakami, Rika AU - Kawakami R FAU - Nakanishi, Michio AU - Nakanishi M FAU - Tanimoto, Keiji AU - Tanimoto K FAU - Usami, Satoru AU - Usami S FAU - Kinoshita, Hideyuki AU - Kinoshita H FAU - Saito, Yoshihiko AU - Saito Y FAU - Nakao, Kazuwa AU - Nakao K LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20061002 PL - England TA - J Mol Cell Cardiol JT - Journal of molecular and cellular cardiology JID - 0262322 RN - 0 (DNA Probes) RN - 0 (Endothelin-1) RN - 0 (RE1-silencing transcription factor) RN - 0 (Repressor Proteins) RN - 0 (Transcription Factors) RN - 85637-73-6 (Atrial Natriuretic Factor) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases) RN - EC 3.5.1.98 (Hdac5 protein, rat) RN - EC 3.5.1.98 (Histone Deacetylases) SB - IM MH - Animals MH - Atrial Natriuretic Factor/genetics MH - Base Sequence MH - Calcium-Calmodulin-Dependent Protein Kinases/*metabolism MH - Cardiomegaly/etiology/genetics/metabolism MH - DNA Probes/genetics MH - Disease Models, Animal MH - Endothelin-1/pharmacology MH - Histone Deacetylases/classification/genetics/*metabolism MH - Humans MH - In Vitro Techniques MH - Mice MH - Mutation MH - Myocytes, Cardiac/*metabolism MH - Rats MH - Repressor Proteins/genetics/*metabolism MH - Signal Transduction MH - Transcription Factors/genetics/*metabolism EDAT- 2006/10/03 09:00 MHDA- 2007/02/01 09:00 CRDT- 2006/10/03 09:00 PHST- 2006/03/13 00:00 [received] PHST- 2006/07/26 00:00 [revised] PHST- 2006/08/17 00:00 [accepted] PHST- 2006/10/03 09:00 [pubmed] PHST- 2007/02/01 09:00 [medline] PHST- 2006/10/03 09:00 [entrez] AID - S0022-2828(06)00769-3 [pii] AID - 10.1016/j.yjmcc.2006.08.010 [doi] PST - ppublish SO - J Mol Cell Cardiol. 2006 Dec;41(6):1010-22. doi: 10.1016/j.yjmcc.2006.08.010. Epub 2006 Oct 2.