| Project/Area Number |
18390228
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Chiba University |
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Principal Investigator |
SHIOJIMA Ichiro Chiba University, Graduate School of Medicine, Associate professor (90376377)
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| Co-Investigator(Kenkyū-buntansha) |
KOMURO Issei Chiba University, Graduate School of Medicine, Professor (30260483)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,750,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2007: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | cardiac hypertrophy / heart failure / Akt / coronary angiogenesis |
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| Research Abstract |
Using cardiac-specific inducible Aktl transgenic mice, the following points were investigated. 1) Mechanism of the transition from pathological cardiac hypertrophy to heart failure Pathological cardiac hypertrophy was induced by long-term Akt activation in the heart. In this experimental condition, coronary capillary density was reduced and VEGF expression in the heart normally observed in physiological hypertrophy was missing, suggesting that hypoxia in the myocardium contributes to the transition from adaptive cardiac hypertrophy to heart failure. Induction of VEGF expression in physiological hypertrophy was blunted by mTOR inhibitor rapamycin. Thus, dysregulation of Akt-mTOR pathway in the heart may play a causal role in the progression of heart failure under pathological stress. 2) Molecular disntinction between physiological versus pathological cardiac hypertrophy To identify the molecular signature that determines the differences between physiological and pathological cardiac hyp
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ertrophy, DNA microarray analysis was performed to isolate mRNAs that are differentially expressed between these two distinct forms of cardiac hypertrophy. Among differentially expressed genes, we found that molecules involved in fatty acid metabolism were downregulated in the heart with pathological hypertrophy. The expression of PPARγ and PGC-1α, key transcription factors that regulate the expression of fatty acid oxidation genes, were also downregulated by short-term Akt activation, suggesting that Akt regulates cardiac function by modulating glucose/fatty acid metabolism. 3) Therapeutic implications of Akt activation in diseased hearts Short-term Akt activation induces physiological form of cardiac hypertrophy with maintained contractility and increased expression of VEGF in the myocardium. To test the hypothesis that short-term Akt activation improves cardiac function in heart failure. Heart failure was induced by two methods, pressure overload by aortic constriction, and injection of cardiotoxic anti-tumor drug doxorubicin. In both cases, Akt transgene expression was induced when heart failure was established. Short-term Akt activation in these experimental settings improved contractile function, suggesting that Akt activation may be a novel therapeutic strategy for heart failure. Less
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