2004 Fiscal Year Final Research Report Summary
Normalization of increased protein phosphatase 1 activity by using an high efficiency myocardial gene transfer technique in chronic heart failure
| 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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| Keywords | chronic heart failure / dilated cardiomyopathy / protein phosphatase 1 / adenovirus vector / adeno-associated virus vector / cardiomyopathic hamster / high-efficiency in vivo myocardial gene transfer |
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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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Research Products
(8 results)
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[Journal Article] Defective regulation of inter-domain interaction within the ryanodine receptor plays a key role in the pathogenesis of heart failure2005
Author(s)
Oda T, Yano M, Yamamoto T, Tokuhisa T, Okuda, S, Doi M, Ohkusa T, Ikeda Y, Kobayashi, S, Ikemoto N, Matsuzaki M
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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