2011 Fiscal Year Final Research Report
Development of novel therapeutic strategy for heart failure which targets aberrant phosphorylation status in the sarcoplasmic reticulum of failing hearts
| Project/Area Number |
21590932
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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 山口大学, 大学院・医学系研究科, 助教 (00260349)
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| Co-Investigator(Kenkyū-buntansha) |
YANO Masafumi 山口大学, 医学部附属病院, 講師 (90294628)
YAMAMOTO Takeshi 山口大学, 大学院・医学系研究科, 助教 (50363122)
MATSUZAKI Masunori 山口大学, 大学院・医学系研究科, 教授 (60116754)
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| Research Collaborator |
宮崎 要介 山口大学, 大学院生
青山 英和 山口大学, 大学院生
白石 宏造 山口大学, 大学院生
西野 静香 山口大学, 技術補佐員
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| Project Period (FY) |
2009 – 2011
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| Keywords | protein phosphatase 1β / adeno-associated virus vector / gene therapy / RNAi |
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| Research Abstract |
The targeting of Ca^<2+> cycling has emerged as a potential therapy for the treatment of severe heart failure. These approaches include gene therapy directed at overexpressing sarcoplasmic reticulum(SR) Ca^<2+> ATP_ase, or ablation of phospholamban(PLN) and associated protein phosphatase 1(PP1) protein complexes. We previously reported that PP1, one of the PP1 catalytic subunits, predominantly suppresses Ca^<2+> uptake in the SR among the three PP1 isoforms, thereby contributing to Ca^<2+> downregulation in failing hearts. In the present study, we investigated whether heart-failure-inducible PP1-inhibition by adeno-associated viral-9(AAV9) vector mediated gene therapy is beneficial for preventing disease progression in genetic cardiomyopathic mice. In the MLPKO mice, inducible PP1shRNA delivery preferentially ameliorated left ventricular diastolic function and mitigated adverse ventricular remodeling. Heart failure-inducible molecular targeting of PP1 has potential as a novel therapeutic strategy for heart failure.
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Research Products
(35 results)
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[Journal Article] Heart Failure-Inducible Gene Therapy Targeting Protein Phosphatase 1 Prevents Progressive Left Ventricular Remodeling PLoS ONE2012
Author(s)
MiyazakiY, Ikeda Y, Shiraishi K, Fujimoto N. S., Aoyama H, Yoshimura K, Inui M, Hoshijima M, Kasahara H, Aoki H, and Matsuzaki. M
Volume
7(4)
Pages
35875
DOI
Peer Reviewed
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[Journal Article] Tenascin-C is expressed in abdominal aortic aneurysm tissue with an active degradation process2011
Author(s)
Kimura T, Yoshimura K, Aoki H, Imanaka-Yoshida K, Yoshida T, Ikeda Y, Morikage N, Endo H, Hamano K, Imaizumi T, Hiroe M, Aonuma K, Matsuzaki M
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Journal Title
Pathol Int
Volume: 61(10)
Pages: 559-564
Peer Reviewed
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[Journal Article] Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant Ca channel release leading to catecholaminergic polymorphic ventricular tachycardia2011
Author(s)
Suetomi T, Yano M, Uchinoumi H, Fukuda M, Hino A, Ono M, Xu X, Tateishi H, Okuda S, Doi M, Kobayashi S, Ikeda Y, Yamamoto T, Ikemoto N, Matsuzaki M
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Journal Title
Circulation
Volume: 124(6)
Pages: 682-94
Peer Reviewed
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[Journal Article] TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts Biochem Biophys Res Commun2011
Author(s)
Kitajima N, Watanabe K, Morimoto S, Sato Y, Kiyonaka S, Hoshijima M, Ikeda Y, Nakaya M, Ide T, Mori Y, Kurose H
Volume
409(1)
Pages
108-13
Peer Reviewed
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[Journal Article] Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor2010
Author(s)
Uchinoumi H, Yano M, Suetomi T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M
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Journal Title
Circ Res. 2010 Apr 30
Volume: 106(8)
Pages: 1413-24
Peer Reviewed
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[Journal Article] Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction2010
Author(s)
Xu X, Yano M, Uchinoumi H, Hino A, Suetomi T, Ono M, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Ikeda Y, Ikemoto N, Matsuzaki M
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Journal Title
Biochem Biophys Res Commun. 2010 Apr 9
Volume: 394(3)
Pages: 660-6
Peer Reviewed
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[Journal Article] Ischemic pre-conditioning enhances the mobilization and recruitment of bone marrow stem cells to protect against ischemia/ reperfusion injury in the late phase2009
Author(s)
Kamota T, Li TS, Morikage N, Murakami M, Ohshima M, Kubo M, Kobayashi T, Mikamo A, Ikeda Y, Matsuzaki M, Hamano K
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Journal Title
J Am Coll Cardiol
Volume: 53(19)
Pages: 1814-22
Peer Reviewed
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[Presentation] Mutation-linked defective domain interaction within the ryanodine receptor causes ca2+ leak leading to catecholaminergic polymorphic ventricular tachycardia2010
Author(s)
Suetomi T, Yano M, Fukuda M, Hino A, Ono M, Xu X, Susa T, Uchinoumi H, Oda T, Okuda S, Kobayashi S, Yamamoto T, Ikeda Y, Matsuzaki M
Organizer
83rd Scientific Session of American Heart Association
Place of Presentation
Chicago, U. S. A.
Year and Date
20101115-17
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[Presentation] Isoform-specific role of prote in phosphatase 1 catalytic subunits in sarcoplasmic reticulum-mediated ca2+ cycling2010
Author(s)
Ikeda Y, Aoyama H, Miyazaki Y, Shiraishi K, Yoshimura K, Nishino S, Yamamoto T, Yano M, Inui M, Aoki H, Matsuzaki M
Organizer
19th International Conference of the Cardiovascular System Dynamics Society
Place of Presentation
Fukuoka, Centennial Hall Kyushu University School of Medicine
Year and Date
20100923-26
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[Presentation] Decreased affinity of calmodulin to RyR2 may be a sauce mechanism of leaky channel in CPVT-associated mutation2009
Author(s)
Xu X, Yano M, Hino A, Suetomi T, Ono M, Uchinoumi H, Oda T, Doi M, Okuda S, Kobayashi S, Ikeda Y, Yamamoto T, Ohkusa T, Matsuzaki M
Organizer
82nd Scientific Session of American Heart Association
Place of Presentation
Orlando, U. S. A.
Year and Date
20091116-18
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[Presentation] Mutation-linked channel disorder in catecholaminergic polymorphic ventricular tachycardia(CPVT) is caused by abnormally tight domain-domain interaction in RyR22009
Author(s)
Suetomi T, Yano M, Hino A, Ono M, Xu X, Susa T, Uchinoumi H, Oda T, Doi M, Okuda S, Kobayashi S, Ikeda Y, Yamamoto T, Matsuzaki M
Organizer
82nd Scientific Session of American Heart Association
Place of Presentation
Orlando, U. S. A.
Year and Date
20091116-18
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[Presentation] Tenascin-c has a protective role during the development of abdominal aortic aneurysm2009
Author(s)
Kimura T, Yoshimura K, Aoki H, Ikeda Y, Imanaka-Yoshida K, Yoshida T, Hamano K, Hiroe M, Aonuma K, Matsuzaki M
Organizer
82nd Scientific Session of American Heart Association
Place of Presentation
Orlando, U. S. A.
Year and Date
20091116-18
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