| Project/Area Number |
17590729
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Kyoto University |
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Principal Investigator |
HARADA Masaki Kyoto University, Graduate School of Medicine, Assistant Prefessor, 医学研究科, 助手 (30342695)
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| Co-Investigator(Kenkyū-buntansha) |
NAKANISHI Michio Kyoto University, Graduate School of Medicine, Investigator, 医学研究科, 医員 (60378726)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | heart failure / energy consumption / mitochondria / NRSF / PPAR |
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| Research Abstract |
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 the attenuation of NRSF-mediated repression contributes to the reactivation of fetal gene expression during cardiac hypertrophy or heart failure. Transgenic mice expressing a dominant-negative NRSF mutant (dnNRSF) in their hearts exhibit dilated cardiomyopathy and sudden arrhythmic death. Taken together, the regulation of NRSF-HDAC repressor activity plays a key role in the signaling pathways involved in the progression of heart failure and sudden death. In this research, it was revealed that class II HDACs (HDAC4 and 5), which are Ca/calmodulin-dependent kinase (CaMK)-responsive repressors of hypertrophic signaling, also associate with NRSF and participate in NRSF-mediated repression. Blockade of the CaMK-class II HDAC signaling pathway using a CaMK-resistant mutant, a CaMK inhibitor (KN62) or a dominant-negative CaMK mutant inhibited endothelin-1-induced ANP promotor activity, but that inhibitory effect was abolished by mutation of the NRSE within the ANP promoter. In addition, adenovirus-mediated expression of a dominant negative NRSF mutant abolished the inhibitory effect of KN62 on endothelin-1-inducible endogenous ANP gene expression in cultured ventricular myocytes. Finally, the interaction between NRSF and class II HDACs was disrupted in a mouse model of pressure overload-induced cardiac hypertrophy.
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