Anti-inflammatory and anti-coagulant function of ADAMTS13 expressed under blood flow

2011 Fiscal Year Final Research Report

• Project/Area Number: 21592313
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: Nara Medical University
• Principal Investigator: NISHIO Kenji 奈良県立医科大学, 医学部, 准教授 (60254489)
• Project Period (FY): 2009 – 2011
• Keywords: VWF / ADAMTS13

Research Abstract

The function of von Willebrand factor(VWF) is essential for normal hemostasis and regulated by ADAMTS13 which cleaves VWF to smaller less-active forms. We recently found that ADAMTS13 limits thrombus growth at the on-going thrombus generation process, leading speculation that the excessive function of VWF mediated by ADAMTS dysfunction may link to arterial thrombosis in the microcirculation in many diseases.
We investigated the effects of ADAMTS13 on ischemia-reperfusion injury using a 30-minute middle cerebral artery occlusion(MCAO) model in Adamts13-/-and wild-type mice. After reperfusion, the regional cerebral blood flow in the ischemic cortex was decreased markedly in Adamts13-/-mice compared to wild-type mice, which also resulted in a larger infarct volume for Adamts13-/-. Furthermore, brain ischemia induced more prominent activation of inflammatory cells co-expressing high-mobility group box1(HMGB1) and myeloperoxidase(MPO) in the cortical ischemic penumbra of Adamts13-/-mice. Thus, Adamts13 gene deletion aggravated ischemic brain damage, suggesting that ADAMTS13 may protect the brain from ischemia and inflammation by regulating VWF-platelet interactions after reperfusion.
Moreover, a recombinant human ADAMTS13 infused to wild type mice before 4 hours' occlusion significantly reduced infarct volume without cerebral bleeding complications. These results indicate that ADAMTS13 could be an anti-inflammatory and anti-coagulant agent for prevention or treatment for many diseases, especially for stroke.

Research Products

• [Journal Article] ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia-reperfusion injury (2012)
  • Author(s): Masayuki Fujioka, Takafumi Nakano, Kazuhide Hayakawa, Keiichi Irie, Yoshiharu Akitake, Yuya Sakamoto, Kenichi Mishima, Carl Muroi, Yasuhiro Yonekawa, Fumiaki Banno, Koichi Kokame, Toshiyuki Miyata, Kenji Nishio, Kazuo Okuchi, Katsunori Iwasaki, Michihiro
  • Journal Title: Neurol Sci
  • DOI: DOI:10.1007/s10072-011-0913-9
  • Peer Reviewed
• [Journal Article] ADAMTS13欠損マウスを用いた脳虚血再灌流障害の解析 (2011)
  • Author(s): 西尾健治
  • Journal Title: 血栓と循環 Volume: 19(2) Pages: 250-253
• [Journal Article] ADAMTS13の脳梗塞治療薬としての可能性 (2010)
  • Author(s): 西尾健治
  • Journal Title: 血栓止血誌 Volume: 21(4) Pages: 405-408
  • Peer Reviewed
• [Journal Article] ADAMTS13 gene deletion aggravates ischemic brain damage : a possible neuroprotective role of ADAMTS13 by ameliorating postischemic hypoperfusion (2010)
  • Author(s): Fujioka M, Hayakawa K, Mishima K, Kunizawa A, Irie K, Higuchi S, Nakano T, Muroi C, Fukushima H, Sugimoto M, Banno F, Kokame K, Miyata T, Fujiwara M, Okuchi K, and Nishio K
  • Journal Title: Blood Volume: 115 Pages: 1650-1653
  • Peer Reviewed
• [Presentation] The Ratio of ADAMTS13 to VWF-Propeptide Can Reflect the Disease Severity and the Extent of Inflammation of the Patients with Severe Sepsis or Septic Shock (2011)
  • Author(s): Fukushima H, Nishio K, Watanabe T, Seki T, Matsui H, Sugimoto M, Matsumoto M, Fujimura Y, Okuchi K
  • Organizer: 53^<th> American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: San Diego
  • Year and Date: 2011-12-12
• [Presentation] PROTECTIVE PROPERTY OF ADAMTS13 IN A MOUSE-MODEL OF ISCHEMIC STROKE XXII (2009)
  • Author(s): K. Nishio, M. Fujioka, K. Hayakawa, K. Mishima, M. Fujiwara, F. Banno, K. Kokame, T. Miyata, Y. Shida, M. Sugimoto, T. Ueyama, H. Fukushima, K. Okuchi
  • Organizer: Congress of The International Society on Thrombosis and Haemostasis
  • Place of Presentation: Boston
  • Year and Date: 20090711-16
• [Presentation] 脳梗塞モデルに対するADAMTS13の効果-マウスを用いたin vivo実験系による検討- (2009)
  • Author(s): 西尾健治, 藤岡政行, 福島英賢, 植山徹, 坂野史明, 小亀浩市, 宮田敏行, 奥地一夫
  • Organizer: 37回日本救急医学総会
  • Place of Presentation: 盛岡市
  • Year and Date: 2009-10-30
• [Presentation] ADAMTS13の神経保護作用-脳虚血再灌流障害マウスモデルを用いて- (2009)
  • Author(s): 西尾健治、藤岡政行、福島英賢、奥地一夫、坂野史明、小亀浩市、宮田敏行
  • Organizer: 第32回日本血栓止血学会学術集会
  • Place of Presentation: 小倉
  • Year and Date: 2009-06-06