心筋細胞肥大の情報伝達におけるp300=GATA経路の役割

与其他增殖细胞不同，心肌细胞在各种刺激下会增大。因此，心肌细胞的增大导致收缩期心力衰竭，因为心脏是心肌细胞的集合体。由于心力衰竭是高血压心脏病、突发性心肌病和缺血性心脏病等各种心脏病的常见终末表现，因此心力衰竭的治疗在临床环境中可能极其重要。以往的研究表明，神经、体液以及交感神经系统、肾素-血管紧张素系统和内皮素系统中的内分泌因子在应激状态下被激活。这些因子与心肌细胞膜上各自的受体结合，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。当细胞核中某些转录控制因子被激活时，心肌细胞的基因表达模式从成人型转变为胎儿型。这些变化常见于各种因素诱导的心肌细胞增大过程中，与心肌功能障碍密切相关。因此，对这种核内信息传递系统的详细分析，对于在细胞和分子水平上阐明心力衰竭的机制，以及制定心力衰竭的基本治疗策略都是非常有用的。我们首次建立了一种方法，通过将基因直接注射到成年大鼠心肌中，来分析体内对压力过载反应的启动子元件。通过详细评估，我们发现GATA转录因子在心肌细胞扩大过程中基因表达调控中起核心作用，而转录核心激活因子p300与GATA转录因子结合后也参与心肌基因的转录。

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.