title: Class II HDACs mediate CaMK-dependent signaling to NRSF in ventricular myocytes.
abstract: 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.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto Graduate School of Medicine, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto-city, Kyoto 606-8507, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Masaki
authors.initials: M
authors.lastname: Harada
authors.forename: Nobuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuno
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Adachi
authors.forename: Rika
authors.initials: R
authors.lastname: Kawakami
authors.forename: Michio
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanimoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Usami
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D015342:DNA Probes / Q000235:genetics; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000494:pharmacology; D006655:Histone Deacetylases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D009320:Atrial Natriuretic Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D015342:DNA Probes; D019332:Endothelin-1; D006655:Histone Deacetylases; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C498619:Hdac5 protein, rat