| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Background : Granulocyte-colony stimulating factor (G), which can increase circulating granulocytes, or myelosuppressives (M), which can suppresse circulating granulocytes, improves post-infarct (MI) cardiac function and remodeling and reduces old infarct size. The combination of these drugs may have synergy under less increase of granulocytes.
Method and Results : MI was induced by 30-min ischemia and reperfusion (Day 0) in rabbits, and G (10 ug/kg of G treated with from Day 3 to 7), myelosuppressives (M,15 mg/kg/day of 5-fluorouracil and 20 mg/kg/day of cyclophosphamide from Day 1 to 2), both (G+M), or saline (S). Other rabbits with the above procedures were treated with AMD3100 (20ug/kg/day), a specific CXCR4 antagonist, from Day 1 to 7. Improvements of ejection fraction and end-diastolic dimension were greatest in M+G (EF/EDD=73±3%/9.8±0.7mm) and greater in G (63±4%/11.2±0.6mm) and in M (EF/EDD=62±3%/11.8±1.1mm) than in S (56±5%/13.6±1.0mm), and scar area/left ventricle wall area ratio was smallest in M+G on day 28. CD34+/CXCR4^+-cells in peripheral blood and SDF-1,a chemoattractant of circulating CXCR4+ cells, CD34+/CXCR4^+-cell mobilization, matrix metalloprotemase-1 (a collagenase) in MI tissues and DiI-labeled bone marrow-derived myofibroblast and cardiomyocytes were greatest in G+M and greater in G and in M than in S. AMD 3100 inhibited all of them. Circulating granulocytes was significantly decreased in G+M than in G.
Conclusion : G+M improves markedly cardiac function and remodeling of post-infarct heart via stimulation of the CXCR4+/SDF-1chemotactic axis under less increase of granulocytes.
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