転写因子GATA-5心筋過剰発現による心不全発症モデルマウスの作成

毫无疑问，收缩性疾病是心力衰竭病理发展的第一步。虽然药物被开发用于缓解收缩期心力衰竭，但已经澄清，它们并不总能改善心脏病的预后。因此，心衰的病理状况应该从一个新的角度来阐明，而不是拘泥于先入为主的观念。此外，有必要建立动物模型来筛选治疗心力衰竭的药物。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。当某些转录控制因子在心肌细胞核中被激活时，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，对于在分子和细胞水平上阐明心力衰竭的机制，以及开发心力衰竭的基本治疗方法非常有用。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。详细评价发现，GATA转录因子特别是GATA-5在心肌细胞扩大过程中基因表达调控中发挥重要作用，而转录核心激活因子p300与GATA-5结合后也参与心肌基因转录。此外，我们最近发现p300/GATA通路靶物质内皮素-1在心肌中过表达后，心肌表达增强，导致心肌肥厚和心力衰竭。少

There is no doubt that a systolic disorder is the initial step during the development of a pathologic condition of heart failure. Although drugs were developed to relieve systolic heart failure, it has been clarified that they do not always improve the prognoses of heart diseases. Therefore, the pathologic condition of heart failure should be clarified from a novel viewpoint without being adhered to preconceived ideas. Moreover, it is necessary to develop animal models for screening drugs to treat heart failure. 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 ce … More ll 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 molecular and cellular levels, as well as for developing basic therapeutic approaches 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, it was found that GATA transcriptional factors, in particular GATA-5, play important roles in the gene expression control during myocardial cell enlargement, and that p300, a transcriptional core activator, is also involved in the myocardial gene transcription after binding to GATA-5. Furthermore, we recently found that the myocardial expression of endothelin-1, a target substance of p300/GATA pathway, was enhanced after the overexpression of p300 in the myocardium, resulting in the induction of cardiac hypertrophy and heart failure. Less