2006 Fiscal Year Final Research Report Summary
Identification of a novel therapeutic target for abdominal aortic aneurysm
| Project/Area Number |
17591337
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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 |
General surgery
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| Research Institution | Yamaguchi University |
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Principal Investigator |
YOSHIMURA Koichi Yamaguchi University, School of Medicine, Research Associate, 医学部, 助手 (00322248)
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| Co-Investigator(Kenkyū-buntansha) |
AOKI Hiroki Yamaguchi University, School of Medicine, Associate Professor, 医学部, 助教授 (60322244)
FURUTANI Akira Yamaguchi University, School of Medicine, Assistant Professor, 医学部附属病院, 講師 (90346552)
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| Project Period (FY) |
2005 – 2006
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| Keywords | aortic aneurysm / therapy / JNK / extracelular matrix / regression |
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| Research Abstract |
Abdominal aortic aneurysm (AAA) is a common disease that, when surgical treatment is inapplicable, results in rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is eagerly awaited, the destruction of the aortic walls in AAA has been considered an irreversible process. We found that c-Jun N-terminal kinase (JNK) is highly activated in human AAA walls. We also found that JNK activity is essential for the expression of matrix metalloproteinase (MMP)-9 and, concurrently, suppression of the extracellular matrix (ECM) biosynthesis. We therefore investigated the role of JNK in the pathogenesis of AAA in vivo. We created a mouse AAA model by periaortic application of CaC12, which was accompanied by activation of JNK and MMPs, and suppression of lysyl oxidase (LOX), which is an essential biosynthetic enzyme for collagen and elastin fibers. Our data indicate that, in addition to MMP activities, suppression of ECMbiosynthesis may contribute to the AAA pathogenesis because local LOX gene delivery prevented AAA formation. Treatment of mice with SP600125, a specific JNK inhibitor, completely abrogated the formation of CaCl2induced AAA. Furthermore, SP600125 treatment after the establishment of AAAcaused a reduction in the aortic diameters with normalized tissue architecture. SP600125 treatment also caused significant regression of angiotensin II-induced AAA in ApoE-null mice after its establishment, as demonstrated by serial ultrasonographic studies in live animals. These data demonstrate that JNK dictates the abnormal ECM metabolism in AAA pathogenesis by enhancing tissue degradation and suppressing tissue repair. Therefore, inhibition of JNK may provide a novel therapeutic option for AAA.
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