| Project/Area Number |
17590769
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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 | Kurume University |
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Principal Investigator |
NAGATA Tsuyoshi Kurume University, School of Medicine, Assistant Professor, 医学部, 助手 (70289429)
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| Co-Investigator(Kenkyū-buntansha) |
YASUKAWA Hideo Kurume University, Cardiovascular Research institute, Assistant Professor, 循環器病研究所, 講師 (60289361)
KAI Hisashi Kurume University, School of Medicine, Associate Professor, 医学部, 助教授 (60281531)
MORI Takahiro Kurume University, School of Medicine, Assistant Professor, 医学部, 助手 (80389254)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | remodeling / biomechanical stress / ischemia / gp130 / SPRR1A / MAP kinase / 心肥大 / 再環流障害 / 圧負荷 / 心筋肥大 / 心筋アポトーシス |
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| Research Abstract |
The interleukin-6 cytokines, acting via gp130 receptor pathways, play a pivotal role in the reduction of cardiac injury induced by mechanical stress or ischemia and in promoting subsequent adaptive remodeling of the heart. We have now identified the small proline-rich repeat proteins (SPRR) 1A and 2A as downstream targets of gp130 signaling that are strongly induced in cardiomyocytes responding to biomechanical/ischemic stress. Upregulation of SPRR1A and 2A was markedly reduced in the gp130 cardiomyocyte-restricted knockout mice. In cardiomyocytes, MEK1/2 inhibitors prevented SPRR1A upregulation by gp130 cytokines. Furthermore, binding of NF-IL6 (C/EBPbeta) and c-Jun to the SPRR1A promoter was observed after CT-1 stimulation. Histological analysis revealed that SPRR1A induction after mechanical stress of pressure overload was restricted to myocytes surrounding piecemeal necrotic lesions. A similar expression pattern was found in postinfarcted rat hearts. Both in vitro and in vivo ectopic overexpression of SPRR1A protected cardiomyocytes against ischemic injury. Thus, this study identifies SPRR1A as a novel stress-inducible downstream mediator of gp 130 cytokines in cardiomyocytes and documents its cardioprotective effect against ischemic stress.
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