| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2000: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1999: ¥9,500,000 (Direct Cost: ¥9,500,000)
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| Research Abstract |
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
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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
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