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Reductionof endothelial tight junction proteins on experimental cerebral aneurysm in rats

Research Project

Project/Area Number 20591686
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionThe University of Tokushima

Principal Investigator

NISHI Kyoko (2009-2010)  The University of Tokushima, 大学院・ヘルスバイオサイエンス研究部, 講師 (60335817)

中嶌 教夫 (2008)  The University of Tokushima, 大学院・ヘルスバイオサイエンス研究部, 助教 (00332817)

Co-Investigator(Kenkyū-buntansha) NAGAHIRO Shinji  徳島大学, 大学院・ヘルスバイオサイエンス研究部, 教授 (60145315)
KANEMATSU Yasuhisa  徳島大学, 病院, 助教 (90363142)
UNO Masaaki  徳島大学, 大学院・ヘルスバイオサイエンス研究部, 准教授 (90232884)
MATSUBARA Shunji  徳島大学, 病院, 講師 (60294675)
YAGI KENJI  徳島大学, 大学院・ヘルスバイオサイエンス研究部, 助教 (80551837)
TADA Yoshiteru  徳島大学, 病院, 助教 (30547964)
西 京子  徳島大学, 大学院・ヘルスバイオサイエンス研究部, 講師 (60335817)
Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2010: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000)
Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords脳動脈瘤 / タイトジャンクション蛋白 / mineral corticoid receptor / phosphodiesterase / 血管内皮障害 / angiotensin II / エストロゲン / 炎症 / ラット / cccludin / ZO-1 / マクロファージ
Research Abstract

The formation of cerebral aneurysms is associated with endothelial damage and macrophage migration. Hypothesizing that the opening of tight junctions (TJs) due to the disappearance of the TJ proteins occludin and zona occludens-1 (ZO-1) in damaged endothelia facilitates macrophage migration, leading to cerebral aneurysm formation, we investigated the role of TJ proteins. To induce cerebral aneurysms, we used female rats subjected to hypertension (HT), oophorectomy (OVX), and hemodynamic stress and evaluated the vascular wall morphologically, immunohistochemically, and by quantitative RT-PCR. We also assessed the regulation of TJ proteins in human brain endothelial cells (HBECs). In the very early stage before aneurysm formation, the expression of occludin and ZO-1was reduced in injured endothelial cell junctions exhibiting gaps. In the course of aneurysmal progression their reduction progressed and was correlated with macrophage migration. In HT+OVX rats we observed an increase in angiotensin II and the degradation molecules matrix metalloproteinase-9 (MMP-9), nicotinamide-adenine dinucleotide phosphate oxidases, and monocyte chemoattractant protein-1. The mineralocorticoid receptor blocker eplerenone increased occludin and ZO-1expression; this was associated with a reduction in angiotensin II and the degradation molecules and resulted in the inhibition of macrophage exudation and aneurysm formation. In HBECs, occludin and ZO-1down-regulation by angiotensin II and estrogen deficiency was reversed by eplerenone, the MMP inhibitor SB3CT, and apocynin. Our results suggest that macrophage migration is associated with the reduction in TJ proteins induced by the degradation molecules.

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (17 results)

All 2011 2010 2009 2008 Other

All Journal Article (7 results) (of which Peer Reviewed: 2 results) Presentation (8 results) Remarks (2 results)

  • [Journal Article] Statins Promote the Growth of Experimentally-induced Cerebral Aneurysms in Estrogen-Deficient Rats2011

    • Author(s)
      Tada Y, Kitazato KT, Yagi K, Shimada K, Matsushita N, Kinouchi T, Kanematsu Y, Satomi J, Kageji T, Nagahiro S
    • Journal Title

      Stroke in press

    • Related Report
      2010 Final Research Report
  • [Journal Article] Reduction of endothelial tight junction proteins is related to cerebral aneurysm formation in rats.2010

    • Author(s)
      Tada Y, Yagi K, Kitazato KT, Tamura T, Kinouchi T, Shimada K, Matsushita N, Nakajima N, Satomi J, Kageji T, Nagahiro S.
    • Journal Title

      J Hypertens. 28

      Pages: 1883-1891

    • Related Report
      2010 Final Research Report
  • [Journal Article] Ibudilast inhibits cerebral aneurysms by down-regulating inflammation-related molecules in the vascular wall of rats.2010

    • Author(s)
      Yagi K, Tada Y, Kitazato KT, Tamura T, Satomi J, Nagahiro S.
    • Journal Title

      Neurosurgery. 66

      Pages: 551-559

    • Related Report
      2010 Final Research Report
  • [Journal Article] Role of mineralocorticoid receptor on experimental cerebral aneurysms in rats.2009

    • Author(s)
      Tada Y, Kitazato KT, Tamura T, Yagi K, Shimada K, Kinouchi T, Satomi J, Nagahiro S.
    • Journal Title

      Hypertension. 54

      Pages: 552-557

    • Related Report
      2010 Final Research Report
  • [Journal Article] Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats.2009

    • Author(s)
      Tamura T, Jamous MA, Kitazato KT, Yagi K, Tada Y, Uno M, Nagahiro S.
    • Journal Title

      J Hypertens. 27

      Pages: 1284-12892

    • Related Report
      2010 Final Research Report
  • [Journal Article] Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator2009

    • Author(s)
      Yagi K
    • Journal Title

      Stroke 4 0

      Pages: 626-631

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Endothelial damage due to impaired NO bioavailability triggers cerebral aneurysm formation in female rats-Endothelial damage and cerebral aneurysm2009

    • Author(s)
      Tamura T
    • Journal Title

      Journal of Hypertension (印刷中)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation] Eplerenone suppresses the progression of experimentally-induced cerebral aneuryss in rats2009

    • Author(s)
      Tada Y., et al
    • Organizer
      XIV World Conress of Neurological Surgery
    • Place of Presentation
      Boston, USA
    • Year and Date
      2009-09-03
    • Related Report
      2009 Annual Research Report
  • [Presentation] Cyclic Nucleotide Phosphodiesterase 4-Related Vascular Inflammation Contributes to the Progression of Cerebral Aneurysms2009

    • Author(s)
      Yagi K, Kitazato KT, Tada Y, Tamura T, Matsuzaki K, Satomi J, Nagahiro S.
    • Organizer
      XIV world Congress of Neurological Surgery
    • Place of Presentation
      Boston, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Eplerenone suppresses the progression of experimentally-induced cerebral aneurysms in rats2009

    • Author(s)
      Tada Y, Kitazato KT, Tamura T, Yagi K, Shimada K, Kinouchi T, Matsushita N, Satomi J, Nagahiro S.
    • Organizer
      XIV world Congress of Neurological Surgery
    • Place of Presentation
      Boston, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Role of mineral corticoid receptor on experimental cerebral aneurysms in rats 20092009

    • Author(s)
      Tada Y, Kitazato KT, Tamura T, Yagi K, Shimada K, Kinouchi T, Satomi J, Nagahiro S.
    • Organizer
      The 6th International Intracranial Stent meeting
    • Place of Presentation
      Sendai, Japan
    • Related Report
      2010 Final Research Report
  • [Presentation] What should we do to prevent cerebral aneurysm formation and progression2008

    • Author(s)
      Nagahiro S, Tamura T, Yagi K, Tada Y, Jamous MA, Uno M, Nakajima N, Matsubara S, Kitazato KT
    • Organizer
      6th World Stroke Congress
    • Place of Presentation
      Vienna, Austria
    • Related Report
      2010 Final Research Report
  • [Presentation] Leucocyte adhesion molecules contribute to the development of cerebral aneurysms in rats2008

    • Author(s)
      Yagi K, Kitazato KT, Tada Y, Tamura T, Nakajima N, Matsubara S, Nagahiro S.
    • Organizer
      6th World Stroke Congress
    • Place of Presentation
      Vienna, Austria
    • Related Report
      2010 Final Research Report
  • [Presentation] Role of mineral corticoid receptor on experimental cerebral aneurysms in rats2008

    • Author(s)
      Tada Y, Kitazato KT, Tamura T, Yagi K, Shimada K, Kinouchi T, Satomi J, Nagahiro S.
    • Organizer
      6th World Stroke Congress
    • Place of Presentation
      Vienna, Austria
    • Related Report
      2010 Final Research Report
  • [Presentation] Edaravone, a free radical scavenger, inhibits MMP-9 related brain hemorrhage in rats treated with tissue plasrainogen activator2008

    • Author(s)
      Uno M
    • Organizer
      Xth International Symposium on Thrombolysis and Acute Stroke Therapy
    • Place of Presentation
      Budapest, Hungary
    • Related Report
      2008 Annual Research Report
  • [Remarks] ホームページ等

    • Related Report
      2010 Final Research Report
  • [Remarks]

    • URL

      http://www.neurosurgerytokushima.com/

    • Related Report
      2008 Annual Research Report

URL: 

Published: 2008-04-01   Modified: 2016-04-21  

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