Molecular Mechanisms of Genetic Response of Myocardial Cells to Cytotoxic Stress

CARP是一种心脏阿霉素反应蛋白，已被鉴定为一种核蛋白，其表达响应于阿霉素而下调。在这项研究中，我们试图研究病理生理应激和CARP基因表达调控之间的联系，以检验CARP作为一种可靠的遗传标记反映体内和体外不同心肌应激反应的假设。CARP表达在三种不同的大鼠心脏肥大模型中显著增加：腹主动脉缩窄、自发性高血压大鼠（SHR）和Dahl盐敏感大鼠。CARP表达在出生后大鼠发育过程中增加，表明CARP表达增加不被认为是“胎儿”基因程序的重新激活。腹腔注射低剂量脂多糖（LPS）诱导大鼠心脏CARP表达，而高剂量LPS抑制其表达。此外，我们发现CARP mRNA 关于我们 在本研究中测试的所有实验模型中，A水平与BNP mRNA水平非常强相关。瞬时转染实验表明，CARP启动子和BNP启动子可被SEK 1或MKK 3的阻遏所激活，SEK 1或MKK 3分别特异性激活JNK/SAPK和p38 MAP激酶。因此，V12 Rac 1a，Rac 1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基因的表达是通过JNK和/或p38 MAP激酶途径协调调节的，并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。鉴于BNP合成增强与心脏超负荷密切相关，应激反应性MAP激酶通路的激活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是心肌细胞应激的一种新的遗传标记。少

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