| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Recent studies have shown that the heart expresses a portfolio of stress-activated cytokines, including tumor necrosis factor, interleukin-6, and cardiotrophin-1 (CT-1) in response to myocardial stress, and these proinflammatory mediators are necessary to confer cytoprotective responses in the heart, which would play important role in the pathogenesis of heart failure. Our recent studies clearly showed that CT-1 expression was increased after hypoxic stimulation and activation of gp130-dependent signaling pathway transduced signals directly relate to cardiac myocyte survival.
Expression of bcl-xL and MnSOD is induced through JAK/STAT pathway, and Akt is activated through phosphatidylinositol 3-kinase in cardiac myocyte after gp130 activation.
VEGF, which plays an important role in the maintenance of cardiac function by restoration of oxygen deprivation during the remodeling process, has been identified as a novel target of STAT3. Transfection of constitutively active form of STAT3 (caSTAT3) by using adenovirus vector increased VEGF expression in cardiac myocyte and the conditioned medium from caSTAT3 transfected cells produced endothelial tubule formation, which was inhibited by anti-VEGF antibody. Transgenic mice with cardiac specific overexpression of caSTAT3 (caSTAT3-TG) exhibited increased expression of VEGF in the hearts, which was accompanied by increased capillary density and VE-cadherin expression. This study suggests that gp130/STAT signaling in cardiac myocyte can control vessel growth and STAT3 is highlighted as a regulator of angiogenic factors.
Signals through gp130 provides new insights into the pathophysiological significance of cytokines in cardiac remodeling and activation of this pathway is proposed as a novel therapeutic strategy for prevention of heart-failure.
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