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，其表达下调是对阿霉素的反应。在这项研究中，我们试图检查病理生理应激和鲤鱼基因表达调控之间的联系，以检验鲤鱼作为一个可靠的遗传标记来反映体内和体外对不同心肌应激的反应的假说。在大鼠心肌肥厚、腹主动脉缩窄、自发性高血压大鼠(SHR)和Dahl盐敏感大鼠三种不同的心肌肥厚模型中，CARP的表达均显著增加。在出生后的大鼠发育过程中，CARP的表达增加，这表明CARP的表达增加并不被认为是“胎儿”基因程序的重新激活。小剂量脂多糖(LPS)诱导大鼠心脏CAP表达，高剂量脂多糖(LPS)抑制其表达。此外，我们还发现鲤鱼mrn…在本研究测试的所有实验模型中，更多的A水平与BNP mRNA水平密切相关。对原代培养的乳鼠心肌细胞的瞬时转染实验表明，CARP启动子和BNP启动子分别被SEK1和MKK3的过度表达所激活，而SEK1和MKK3分别特异性地激活JNK/SAPK和p38 MAP激酶。因此，Vl2racl a，组成活性形式的rac1，诱导鲤鱼和BNP启动子的活性。这些结果表明，鲤鱼和BNP基因的表达是通过JNK和/或p38 MAP激酶途径协同调节的，这可能是这两个基因对各种细胞外刺激的高度调控的原因。鉴于BNP合成增强与心脏超负荷密切相关，而应激反应MAPK通路的激活可能是心力衰竭和心肌肥厚基因表达改变的原因，本研究结果表明，CARP是心肌细胞应激的一个新的遗传标记。较少

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