|Budget Amount *help
¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 1999 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 1998 : ¥2,000,000 (Direct Cost : ¥2,000,000)
The signal transducer and activator of transcription (STAT) 3, a transcriptional factor downstream of several cytokines, is activated by Janus kinase (JAK) families and plays pivotal roles in cardiac hypertrophy through gp130. To determine the physiological significance of STAT3 in vivo, transgenic mice with cardiac-specific overexpression of the Stat3 gene (WT-TG) were generated. WT-TG manifested myocardial hypertrophy at 12 weeks of age with increased expression of the atrial natriuretic factor (ANF), β-myosin heavy chain (MHC) and cardiotrophin (CT) -1 genes. The animals were administered intraperitoneally with 15 mg/kg doxorubicin (Dox), an anti-neoplastic drug with restricted use because of its cardiotoxicity. The survival rates after 10 days were 25% (4/20) for control littermates (Cont), but 80% (16/20) for WT-TG (P<0.01). Dox administration significantly reduced the expression of the cardiac α-actin and Sat3 genes and increased the expression of ANF and β MHC genes which are in
creased in cardiac heart failure in Cont hearts but not in WT-TG. These results provide direct evidence that STAT3 transduces not only hypertrophic signal but also protective signal against Dox-induced cardiomyopathy by inhibiting the reduction of cardiac contractile genes and the induction of cardiac protective factors.
Furthermore, activation of STAT3 induced by CT-1 increased the expression of vascular endothelial growth factor (VEGF)gene. In the WT-TG heart the VEGF gene is up-expressed, whereas in transgenic mice carrying dominant negative STAT3 gene it is down-expressed. These data reveal that STAT3 functions as a regulator of VEGF in the heart.
In summary STAT3 in the heart activated by IL-6, CT-1, which are known to be activated in the condition of congestive heart failure or ischemic heart disease, is concerned with the several self-defensive mechanisms through the production of angiogenic growth factor, cardiac protective factor, and the regulation of cardiac contractile protein Less