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.

高血压等肥厚性刺激启动了许多亚细胞信号通路，最终到达心肌细胞核并改变基因表达模式。在代偿性肥厚向失代偿性心力衰竭过渡过程中，压力过载可显著诱导心肌细胞内皮素-1的表达。鉴定导致这种诱导的核通路将为心力衰竭提供新的药理靶点。作为e1a相关蛋白之一，p300在诱导心肌细胞内皮素-1表达中起关键作用，并作为肥大应答转录因子如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，并参与心肌细胞肥厚刺激诱导的GATA-4的乙酰化和DNA结合。我们培养了心肌特异性过表达野生型p300或突变型p300的转基因小鼠，这些小鼠失去了HAT活性，并发现p300介导的GATA-4乙酰化是体内失代偿性心力衰竭的病理性心肌细胞生长所必需的。最近，一些化合物在体外和培养中抑制p300-HAT活性被报道。其中一种是天然化合物姜黄素，它可以抑制培养的HeLa细胞中的组蛋白乙酰化并抑制p300介导的染色质转录。该化合物抑制pe诱导的肥厚反应，如肌原纤维组织和细胞大小的增加，pe诱导的心脏胎儿基因的反激活，以及pe诱导的GATA-4 DNA结合活性的增加。因此，我们确定了一种靶向心肌细胞压力过载信号传导核通路的药物，可用于体内高血压性心力衰竭的治疗。

项目成果

Expression of p300 protects cardiac myocytes from apoptosis in vivo

• DOI: 10.1016/j.bbrc.2004.01.105
• 发表时间: 2004-03-12
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Kawamura, T;Hasegawa, K;Kita, T
• 通讯作者: Kita, T

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.

Histone acetyltransferase 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;et. al.
• 通讯作者: et. al.