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心筋細胞肥大の情報伝達におけるp300=GATA経路の役割

p300=GATA通路在心肌细胞肥大信号传递中的作用

基本信息

批准号：
11838006
负责人：
HSEGAWA Koji
金额：
$ 2.62万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Differing from other proliferative cells, myocardial cells are enlarged in response to various stimuli. Therefore, the enlargement of myocardial cells results in systolic heart failure because the heart is an aggregate of myocardial cells. Since heart failure is a common terminal image of various heart diseases such as hypertensive heart disease, sudden cardiomyopathy, and ischemic heart diseases, the treatment of heart failure may be extremely important in the clinical setting. Previous studies have clarified that nerves, body fluid, and endocrine factors in the sympathetic nervous system, renin-angiotensin system, and endothelin system are activated under conditions of stress. These factors bind to the respective receptors on the myocardial cell membrane, and the stimulation is finally transferred to the myocardial cell nucleus via various intracellular information transfer systems. When certain transcriptional control factors are activated in the cell nucleus, myocardial cells change their gene expression patterns from the adult type to the fetal type. These changes are commonly observed during myocardial cell enlargement induced by various factors, and are closely associated with myocardial dysfunction. Therefore, detailed analysis of this intranuclear information transfer system is very useful for elucidating the mechanism of heart failure at the cellular and molecular levels, as well as for developing basic therapeutic tactics for heart failure. We established a method of analyzing a promoter element that responds to pressure overload in vivo by directly injecting the gene into the adult rat myocardium for the first time. As the result of detailed evaluation, we found that GATA transcriptional factors play central roles in the gene expression control during myocardial cell enlargement, and that p300, a transcriptional core activator, is also involved in the transcription of the myocardial gene after binding to GATA factors.

与其他增殖细胞不同，心肌细胞对各种刺激反应性增大。因此，心肌细胞的增大导致收缩性心力衰竭，因为心脏是心肌细胞的集合体。由于心力衰竭是各种心脏病如高血压性心脏病、突发性心肌病和缺血性心脏病的常见终末影像，因此心力衰竭的治疗在临床环境中可能极其重要。以往的研究已经阐明，在应激条件下，交感神经系统、肾素-血管紧张素系统和内皮素系统中的神经、体液和内分泌因子被激活。这些因子与心肌细胞膜上的相应受体结合，并且刺激最终通过各种细胞内信息传递系统传递到心肌细胞核。当细胞核中的某些转录控制因子被激活时，心肌细胞将其基因表达模式从成人型改变为胎儿型。这些变化在各种因素引起的心肌细胞增大过程中普遍存在，与心肌功能障碍密切相关。因此，详细分析这一核内信息传递系统对于在细胞和分子水平阐明心力衰竭的机制以及发展心力衰竭的基本治疗策略是非常有用的。我们建立了一种分析启动子元件的方法，在体内的压力超负荷反应的基因直接注射到成年大鼠心肌的第一次。作为详细评估的结果，我们发现加塔转录因子在心肌细胞增大过程中的基因表达控制中起中心作用，并且转录核心激活因子p300在与加塔因子结合后也参与心肌基因的转录。