Investigation on the molecular mechanism of JNK-mediated apoptosis in cardiac myocytes
| Project/Area Number |
14370229
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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 | Yamaguchi University |
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Principal Investigator |
AOKI Hiroki Yamaguchi University, School of Medicine, Associate Professor, 医学部, 客員助教授 (60322244)
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| Co-Investigator(Kenkyū-buntansha) |
IKEDA Yasuhiro Yamaguchi University, School of Medicine, Instructor, 医学部, 寄附講座教員 (00260349)
YOSHIMURA Koichi Yamaguchi University, School of Medicine, Instructor, 医学部, 寄附講座教員 (00322248)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥9,900,000 (Direct Cost: ¥9,900,000)
Fiscal Year 2003: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2002: ¥5,100,000 (Direct Cost: ¥5,100,000)
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| Keywords | oxidative stress / cardiac myocyte / apoptosis / JNK / mitochondria / cytochrome c / caspase / signal transduction / カスパーゼ / c-Jun N-terminal kinase / アデノウイルス・ベクター |
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| Research Abstract |
Although oxidative stress causes activation of c-Jun N-terminal kinase (JNK) and apoptosis in many cell types, how the JNK pathway is connected to the apoptosis pathway is unclear, The molecular mechanism of JNK-mediated apoptosis was investigated in adult rat cardiac myocytes in culture as a model system that is sensitive to oxidative stress. Oxidative stress caused JNK activation, cytochrome c release and apoptosis without new protein synthesis. Oxidative stress-induced apoptosis was abrogated by dominant negative SEK1-mediated inhibition of JNK pathway, whereas activation of JNK pathway by constitutively active SEKI was sufficient to cause apoptosis. Inhibition of caspase-9, an apical caspase in mitochondrial apoptosis pathway, suppressed oxidative stress-induced apoptosis, whereas inhibition of caspase-8 had no effect, indicating that both JNK pathway and mitochondrial apoptosis machinery are central to oxidative stress-induced apoptosis. Both JNK and SEKI localized on mitochondria where JNK was activated by oxidative stress. Furthermore, active JNK phosphorylated several mitochondrial proteins and caused the release of apoptogenic factors such as cytochrome c from isolated mitochondria in a cell-free assay. These findings indicate that the JNK pathway is a direct activator of mitochondrial death machinery without other cellular components and provide a molecular linkage from oxidative stress to the mitochondrial apoptosis machinery. In addition, JNK activates matrix metalloproteinases in vascular smooth muscle cells and macrophages, which regulates tissue remodeling of cardiovascular system
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Report
(3 results)
Research Products
(12 results)
