| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 1998: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1997: ¥4,100,000 (Direct Cost: ¥4,100,000)
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| Research Abstract |
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
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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
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