| Project/Area Number |
15590754
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Yamaguchi University |
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Principal Investigator |
IKEDA Yasuhiro Yamaguchi University, School of Medicine, Research Associate, 医学部, 寄附講座教員 (00260349)
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| Co-Investigator(Kenkyū-buntansha) |
YANO Masafumi Yamaguchi University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (90294628)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | chronic heart failure / dilated cardiomyopathy / protein phosphatase 1 / adenovirus vector / adeno-associated virus vector / cardiomyopathic hamster / high-efficiency in vivo myocardial gene transfer / アデノウイルスベクター / アデノ関連ウイルスベクター / 高効率心筋遺伝子導入 |
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| Research Abstract |
Background : The type 1 protein phosphatase (PP1) has been reported to be overactivated in experimental and human failing hearts, leading to a depression of Ca^<2+> cycling and contractility. We previously reported that increased PP1 activity was also observed in the models of genetic cardiomyopathy, UMX cardiomyopathic(CM) hamster, and in vivo inhibition of PPl by overexpressing inhibitor-2(I-2) improved short-term cardiac function. Method and Results : We here investigated the effect of chronic PP1 inhibition by using high efficiency adeno-associated virus (rAAV-) mediated cardiac I-2 gene delivery on heart failure progression and survival in CM hamster. Endogeonus inhibitor-2 (I-2) was only detected in the microsomal fraction of cardiomyocytes, and adenoviral overexpresion of I-2 preferentially localized in the sarcolemma, suggesting that I-2 is a membrane-bound (m-) endogenous PP1 inhibitor. In addition, PP1 activity following adenovirus I-2 transfection in cardiomyocytes dramatically decreased PP1 activity and augmented Ca^<2+> cycling and cell shortening in cardiomyocytes. rAAV-mediated in vivo cardiac I-2 gene delivery restored cardiac function and extended survival time for 3 months in CM hamsters. Conclusions: These findings suggest that increased m- PP1 in cardiomyocytes is an important contributor of depressed Ca2+ cycling, and inhibition of m- PP1 via inhibitor-2 may provide a new molecular target for the treatment of heart failure.
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