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2006 Fiscal Year Final Research Report Summary

Identification of a novel therapeutic target for abdominal aortic aneurysm

Research Project

Project/Area Number 17591337
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionYamaguchi University

Principal Investigator

YOSHIMURA Koichi  Yamaguchi University, School of Medicine, Research Associate, 医学部, 助手 (00322248)

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)
Project Period (FY) 2005 – 2006
Keywordsaortic aneurysm / therapy / JNK / extracelular matrix / regression
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.

  • Research Products

    (12 results)

All 2007 2006 2005 Other

All Journal Article (11 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Statins reduce NF-κ B Activation and Chemokine Secretion in Human Abdominal Aortic Aneurysm Wall2007

    • Author(s)
      吉村耕一
    • Journal Title

      Circulation Journal 71・Sppll

      Pages: 124

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Stabilization of Extracellular Matrix Antagonizes Proinflammatory Signaling and Prevents Progression of Abdominal Aortic Aneurysm In Vivo2006

    • Author(s)
      吉村耕一
    • Journal Title

      Circulation 114

      Pages: II-281

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Regression of Abdominal Aortic Aneurysm by Inhibition of c-Jun N-Terminal Kinase in Mice2006

    • Author(s)
      吉村耕一
    • Journal Title

      Ann NY Acad Sci 1085

      Pages: 74

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Identification of c-Jun N-Terminal Kinase as a Therapeutic Target for Abdominal Aortic Aneurysm2006

    • Author(s)
      吉村耕一
    • Journal Title

      Ann NY Acad Sci 1085

      Pages: 403

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] c-Jun N-terminal kinase抑制による大動脈瘤薬物治療2006

    • Author(s)
      吉村耕一
    • Journal Title

      脈管学 46

      Pages: 637

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Stabilization of Extracellular Matrix Antagonizes Proinflammatory Signaling and Prevents Progression of Abdominal Aortic Aneurysm In Vivo2006

    • Author(s)
      Yoshimura, K
    • Journal Title

      Circulation 114

      Pages: II-281

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Identification of c-Jun N-terminal kinase as a therapeutic target for abdominal aortic aneurysm.2006

    • Author(s)
      Yoshimura, K
    • Journal Title

      Ann N Y Acad Sci 1085

      Pages: 403-406

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase in mice.2006

    • Author(s)
      Yoshimura, K
    • Journal Title

      Ann N Y Acad Sci 1085

      Pages: 74-81

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase2005

    • Author(s)
      吉村耕一
    • Journal Title

      Nature Medicine 11(12)

      Pages: 1330

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase.2005

    • Author(s)
      Yoshimura, K
    • Journal Title

      Nat Med 11

      Pages: 1330-1338

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Inhibition of c-Jun N-terminal kinase causes regression of experimental aortic aneurysms2005

    • Author(s)
      Yoshimura, K
    • Journal Title

      Circulation 112 (17)

      Pages: U97

    • Description
      「研究成果報告書概要(欧文)」より
  • [Patent(Industrial Property Rights)] コラーゲンまたはエラスチン代謝異常疾患の予防剤および治療剤

    • Inventor(s)
      吉村耕一, 青木浩樹, 松崎益徳
    • Industrial Property Rights Holder
      吉村耕一, 青木浩樹, 松崎益徳
    • Industrial Property Number
      PCT/JP2005/015323
    • Filing Date
      出願20050824
    • Description
      「研究成果報告書概要(和文)」より

URL: 

Published: 2008-05-27  

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