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Development of Strategy of Molecular Cloning of Cardiac-Specific-Gene by use of Adriamycin

阿霉素心脏特异性基因分子克隆策略的开发

基本信息

批准号：
08557048
负责人：
KURABAYASHI Masahiko
金额：
$ 6.46万
依托单位：
Gunma University School of Medicine (1997)The University of Tokyo (1996)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

CARP,a cardiac adriamycin response protein, has been identified as a nuclear protein whose expression is down-regulated in response to adriamycin. In this study, we sought to examine the link between the pathophysiological stress and the regulation of CARP gene expression to specifically test the hypothesis that CARP functions as a nuclear factor mediating genetic response to diverse stress in the heart. CARP expression markedly increased in pressure-overloaded hypertrophy of rat heart. CARP expression increased during rat development, which is in a sharp contrast to the concept that cardiac hypertrophy is accompanied by the reactivation of the "fetal" gene program. Consistent with pressure-depenedent regulation, CARP mRNA was present in greater abundance in left ventricle than in right ventricle. In Dahl salt sensitive rats which exhibits the transition from cardiac hypertrophy to heart failure in a salt dependent manner, CARP mRNA increased during the period of compensatoty cardiac hypertrophy but such an increase in CARP mRNA level was attenuated after overt heart failure developed. Intraperitoneal administration of low dose of lipopolysaccharides(LPS) in rats induced CARP expression in the heart whereas higher dose of LPS repressed its expression despite either equally increased the level of iNOS mRNA.Chronic intravenous injection of adriamycin in rabbits increased CARP mRNA levels in mild heart failure while decreased it when heart failure became severe as assessed by the downregulation of Ca-ATPase mRNA.These results suggest taht CARP expression is differentially regulated depending upon the magnitude of hemodynamic overload and CARP may play a role in regulating gene expression during cardiac adaptation and failure.

CARP 是一种心脏阿霉素反应蛋白，已被鉴定为一种核蛋白，其表达因阿霉素反应而下调。在这项研究中，我们试图检查病理生理应激与 CARP 基因表达调节之间的联系，以专门检验 CARP 作为核因子介导心脏对不同应激的遗传反应的假设。压力超负荷肥厚大鼠心脏中CARP表达显着升高。 CARP表达在大鼠发育过程中增加，这与心脏肥大伴随着“胎儿”基因程序重新激活的概念形成鲜明对比。与压力依赖性调节一致，左心室中 CARP mRNA 的丰度高于右心室。在以盐依赖性方式从心脏肥大转变为心力衰竭的Dahl盐敏感大鼠中，CARP mRNA在代偿性心脏肥大期间增加，但在发生明显的心力衰竭后，CARP mRNA水平的这种增加减弱。大鼠腹腔内给予低剂量脂多糖 (LPS) 会诱导心脏中的 CARP 表达，而较高剂量的 LPS 会抑制其表达，尽管这两种情况均会增加 iNOS mRNA 的水平。通过 Ca-ATPase mRNA 的下调评估，长期静脉注射阿霉素可增加轻度心力衰竭时的 CARP mRNA 水平，而当心力衰竭变得严重时则降低 CARP mRNA 水平。这些结果表明 CARP 的表达根据血流动力学超负荷的程度进行差异性调节，CARP 可能在心脏适应和衰竭期间的基因表达调节中发挥作用。