Identification of intracellular signaling molecules that bind to cardiac p300 during the development of heart failure and its application to pharmacological therapy

心力衰竭发生过程中与心脏p300结合的细胞内信号分子的鉴定及其在药物治疗中的应用

• 批准号: 16390230
• 负责人: HASEGAWA Koji
• 金额: $ 9.15万
• 依托单位: Clinical Research Institute, Kyoto Medical Center, National Hospital Organization
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390230/
• 关键词: cardiac myocyte; transcription; p300; heart failure; cardiac myocyte; transcription; GATA-4; heart failure; hypertrophy

Hypertrophic stimuli such as hypertension initiates a number of subcellular signaling pathways, which finally reach the nuclei of cardiac myocytes and change the pattern of gene expression. The expression of endothelin-1 in cardiac myocytes is markedly induced following pressure overload during the transition from compensated hypertrophy to decompensated heart failure. Identification of nuclear pathways that lead to this induction will provide novel pharmacological targets for heart failure. One of E1A-associated proteins, p300 plays a critical role for the induction of endothelin-1 expression in cardiac myoytes, and serves as a coactivator of hypertrophy-responsive transcriptional factors such as MEF-2 and GATA-4. A p300 protein also possesses histone acetyltransferase (HAT) activity, and is involved in hypertrophic stimuli-induced acetylation and DNA binding of GATA-4 in cardiac myocytes. We have generated transgenic mice with cardiac-specific overexpression of either wild-type p300 or mutant p300 that lose its HAT activity, and found that p300-mediated acetylation of GATA-4 is required for pathological myocyte growth with decompensated heart failure in vivo. Recently, several compounds that inhibit p300-HAT activity in vitro and in culture have been reported. One of these is a natural compound, currcumin, which inhibits histone acetylation in cultured HeLa cells and repress p300-mediated chromatin transcription. This compound repressed PE-induced hypertrophic responses such as myofibrilar organization and increase in cell size, PE-induced transactivation of the cardiac fetal genes, and PE-induced increase in the DNA binding activity of GATA-4. Thus, we identified a pharmacological agent that targets nuclear pathways for pressure overload-signaling in cardiac myocytes, and could be applied for the treatment of hypertension-induced heart failure in vivo.

肥大刺激（例如高血压）引发了许多亚细胞信号通路，最终到达心肌细胞的核并改变了基因表达的模式。在从补偿肥大到代偿性心力衰竭的过渡期间，心肌细胞中内皮素-1在心肌细胞中的表达明显诱导。导致这种诱导的核路道的识别将为心力衰竭提供新颖的药理目标。 P300是E1A相关的蛋白之一，在心脏肌因中诱导内皮素-1表达起着至关重要的作用，并且是肥大响应转录因子（如MEF-2和GATA-4）的共激活因子。 P300蛋白还具有组蛋白乙酰转移酶（HAT）活性，并参与心肌细胞中GATA-4的肥大刺激诱导的乙酰化和DNA结合。我们已经产生了野生型P300或突变体P300的心脏特异性过表达的转基因小鼠，这些小鼠失去了帽子活性，发现P300介导的GATA-4的乙酰化是病理肌细胞生长所必需的，而体内的心脏失败。最近，已经报道了几种在体外和培养中抑制p300胶囊活性的化合物。其中之一是天然化合物咖喱蛋白，它抑制培养的HeLa细胞中组蛋白乙酰化并抑制P300介导的染色质转录。这种复合抑制了PE诱导的肥厚反应，例如肌纤维组织，细胞大小的增加，PE诱导的心脏胎儿基因的反式激活以及PE诱导的GATA-4的DNA结合活性的增加。因此，我们确定了一种药理剂，该药理学剂靶向心肌细胞中的核途径，以使压力超负荷信号，并可以用于治疗体内高血压诱导的心力衰竭的治疗。

项目成果

先端医療シリーズ28

先进医学系列28

• 发表时间: 2004
• 作者: Hirai M;Ono K;Morimoto T;Kawamura T;Wada H;Kita T;Hasegawa K.;Kawamura T. et al.;Ehara N. et al.;Hirai M. et al.;Kawamura T. et al.;Kawamura T. et al.;Ehara N. et al.;宮本昌一
• 通讯作者: 宮本昌一

The possible role of peroxisome proliferator-activated receptor gamma in heart failure.

过氧化物酶体增殖物激活受体γ在心力衰竭中的可能作用。

• 发表时间: 2004
• 期刊: Exp.& Clin Cardiol. 9
• 作者: Hirai M;Ono K;Morimoto T;Kawamura T;Wada H;Kita T;Hasegawa K.;Kawamura T. et al.;Ehara N. et al.;Hirai M. et al.;Kawamura T. et al.;Kawamura T. et al.;Ehara N. et al.
• 通讯作者: Ehara N. et al.

Histone acetyltranferase activity of p300 is required for the promotion of left ventricular remodeling following myocardial infarction in adult mice in vivo.

p300 的组蛋白乙酰转移酶活性是促进成年小鼠体内心肌梗塞后左心室重塑所必需的。

• 发表时间: 2006
• 期刊: Circulation 113
• 作者: Miyamoto S;Kawamura T;Morimoto T;Ono K;Wada H;Kawase Y;Matsumori A;Nishio R;Kita T;Hasegawa K.
• 通讯作者: Hasegawa K.

Endothelin-l-dependent nuclear factor of activated T lymphocyte signaling associates with transcriptional coactivator p300 in the activation of the B cell leukemia-2 promoter in cardiac myocytes.

激活的 T 淋巴细胞信号转导的内皮素-1 依赖性核因子与转录共激活因子 p300 相关，激活心肌细胞中的 B 细胞白血病-2 启动子。

• 发表时间: 2004
• 期刊: Circulation Research 94
• 作者: Kawamura T;Ono K;Morimoto T et al.
• 通讯作者: Morimoto T et al.

Down-regulation of endothelin-1 and alteration of apoptosis signaling following left ventricular volume reduction surgery in heart failure of adult rats.a

成年大鼠心力衰竭左心室减容手术后内皮素-1 的下调和细胞凋亡信号的改变。

• 发表时间: 2004
• 期刊: J Cardiovasc Pharmacol 44
• 作者: Hirai M;Ono K;Morimoto T;Kawamura T;Wada H;Kita T;Hasegawa K.;Kawamura T. et al.
• 通讯作者: Kawamura T. et al.