Molecular Mechanisms of Genetic Response of Myocardial Cells to Cytotoxic Stress

心肌细胞对细胞毒性应激的遗传反应的分子机制

基本信息

批准号：
09470161
负责人：
KURABAYASHI Masahiko
金额：
$ 4.16万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470161/
关键词：
Heart Stress CARP Transcription Gene Hypertrophy Heart Failure Endothelin アドリアマイシンプロモーター TGFβ Smad 細胞外マトリックス Mn-SOD 酸化ストレスサイトカイン NFkB BTEB2

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 test the hypothesis that CARP serves as a reliable genetic marker that reflects a response to diverse myocardiac stresses in vivo and in vitro. CARP expression was markedly increased in three distinct models of cardiac hypertrophy in rat ; constriction of abdominal aorta, spontaneously hypertensive rats (SHR) and Dahl salt- sensitive rats. CARP expression was increased during postnatal rat development, indicating that increased CARP expression is not considered to be the reactivation of the "fetal" gene program. Intraperitoneal administration of low dose of lipopolysaccharides (LPS) in rats induced CARP expression in the heart whereas higher dose of LPS repressed its expression. In addition, we found that CARP mRN … More A levels correlated very strongly with the BNP mRNA levels in all the experimental models tested in this study. Transient transfection assays into primary cultures of neonatl rat cardiac myocytes indicate that CARP promoter as well as BNP promoter is stimulated by overepression of SEK1 or MKK3, which specifically activates JNK/SAPK and p38 MAP kinase, respectively. As such, Vl2Racl a, constitutively active form of Rac1, induced CARP and BNP promoter activity. These results suggest that expression of CARP and BNP genes is coordinately regulated through JNK and/or p38 MAP kinase pathways, and may account for a highly regulated expression of these two genes in response to a variety of extracellular stimuli. Given that enhanced BNP synthesis is closely associated with cardiac overload, and activation of stress-responsive MAP kinase pathways may account for the altered gene expression in heart failure and cardiac hypertrophy, the findings in the present study suggest that CARP represents a novel genetic marker of myocardial cellular stress. Less

CARP 是一种心脏阿霉素反应蛋白，已被确定为一种核蛋白，其表达因阿霉素反应而下调，在本研究中，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。假设 CARP 是一种可靠的遗传标记，反映了体内和体外对不同心肌应激的反应，在三种不同的腹主动脉收缩模型中，CARP 表达显着增加；自发性高血压大鼠（SHR）和 Dahl 盐敏感大鼠在出生后发育过程中 CARP 表达增加，表明 CARP 表达增加不被认为是腹膜内施用低剂量脂多糖的重新激活。 LPS) 诱导大鼠心脏中的 CARP 表达，而较高剂量的 LPS 则抑制其表达。此外，我们发现 CARP mRNA 水平与 BNP mRNA 水平密切相关。在本研究测试的所有实验模型中，瞬时转染至新生儿测定大鼠心肌细胞的原代培养物中表明，CARP 启动子和 BNP 启动子受到 SEK1 或 MKK3 的过度表达的刺激，SEK1 或 MKK3 特异性激活 JNK/SAPK 和 p38 MAP 激酶，因此，Vl2Racl a（Rac1 的组成型活性形式）诱导 CARP 和 BNP 启动子活性。这些结果表明 CARP 和 BNP 基因的表达。通过 JNK 和/或 p38 MAP 激酶途径协调调节，并且可能解释了这两个基因在响应各种细胞外刺激时的高度调节表达，因为 BNP 合成的增强与心脏超负荷和应激激活密切相关。 -反应性 MAP 激酶通路可能是心力衰竭和心脏肥大中基因表达改变的原因，本研究的结果表明 CARP 代表了心肌细胞应激的一种新的遗传标记。