Identification of Nuclear Signaling Pathways That Lead to the Development of Heart Failure

识别导致心力衰竭发展的核信号通路

• 批准号: 14370224
• 负责人: HASEGAWA Koji
• 金额: $ 8.96万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370224/
• 关键词: cardiac myocyte; transcription; GATA-4; p300; heart failure; hypertrophy; acetylation

The purpose of the present study is to identify nuclear signaling pathways that lead to the development of heart failure. Our previous studies demonstrate that a cardiac zinc finger protein GATA-4 is one of the transcriptional factors that regulate hypertrophic responses in cardiac myocytes. The full transcriptional activity of GATA-4 requires its interaction with an adenovirus associated protein, p300. A p300 protein is one, of intrinsic histone acetyltransferases (HAT) and governs gene expression patterns by being recruited to target genes through association with specific transcription factors. HAT activity of p300 is required for acetylating a subset of transcription factors as well as promoting a transcriptionally active chromatin configuration. We show here that p300,is involved in hypertrophic stimuli-induced acetylation and DNA binding of GATA-4 in cardiac myocytes. In addition, we demonstrate that cardiac overexpression of p300 promotes LV remodeling following MI in adult mice in vivo and that HAT activity of p300 is required for these processes. The findings suggest that pharmacological inhibition of p300/GATA-4 transcriptional pathway could be a novel strategy for the treatment of decompensated heart failure in vivo.

本研究的目的是确定导致心力衰竭发展的核信号通路。我们之前的研究表明，心脏锌指蛋白GATA-4是调节心肌细胞肥厚反应的转录因子之一。GATA-4的完全转录活性需要与腺病毒相关蛋白p300相互作用。p300蛋白是内在组蛋白乙酰转移酶（HAT）的一种，通过与特定转录因子的关联被招募到靶基因，从而控制基因表达模式。p300的HAT活性是转录因子子集乙酰化以及促进转录活性染色质结构所必需的。我们在这里表明p300参与心肌细胞中肥大刺激诱导的GATA-4的乙酰化和DNA结合。此外，我们证明了p300的心脏过表达促进了成年小鼠心肌梗死后的左室重构，而p300的HAT活性是这些过程所必需的。这些发现表明，药物抑制p300/GATA-4转录途径可能是体内治疗失代偿性心力衰竭的一种新策略。

项目成果

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Yanazume T、Hasekawa K、Wada H、Morimoto T、Abe M、Kawamura T、Sasayama S.：“心肌细胞肥大期间，细胞外信号调节激酶/GATA-4 的激活需要 Rho/ROCK 途径。”J Biol

Yanazume T, Hasegawa K, Morimoto T, Kawamura T, Wada H, Matsumori A, Kawase Y, Hirai M, Kita T.: "Cardiac p300 is involved in myocyte growth with decompensated heart failure."Mol Cell Biol. 23. 3593-3606 (2003)

Yanazume T、Hasekawa K、Morimoto T、Kawamura T、Wada H、Matsumori A、Kawase Y、Hirai M、Kita T.：“Cardiac p300 参与失代偿性心力衰竭的心肌细胞生长。”Mol Cell Biol。

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