Neurological Sciences

, Volume 33, Issue 5, pp 1107–1115

ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia–reperfusion injury

  • 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 Fujiwara
  • Bo K. Siesjö
Original Article

DOI: 10.1007/s10072-011-0913-9

Cite this article as:
Fujioka, M., Nakano, T., Hayakawa, K. et al. Neurol Sci (2012) 33: 1107. doi:10.1007/s10072-011-0913-9

Abstract

Highly adhesive glycoprotein von Willebrand factor (VWF) multimer induces platelet aggregation and leukocyte tethering or extravasation on the injured vascular wall, contributing to microvascular plugging and inflammation in brain ischemia–reperfusion. A disintegrin and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) cleaves the VWF multimer strand and reduces its prothrombotic and proinflammatory functions. Although ADAMTS13 deficiency is known to amplify post-ischemic cerebral hypoperfusion, there is no report available on the effect of ADAMTS13 on inflammation after brain ischemia. We investigated if ADAMTS13 deficiency intensifies the increase of extracellular HMGB1, a hallmark of post-stroke inflammation, and exacerbates brain injury after ischemia–reperfusion. ADAMTS13 gene knockout (KO) and wild-type (WT) mice were subjected to 30-min middle cerebral artery occlusion (MCAO) and 23.5-h reperfusion under continuous monitoring of regional cerebral blood flow (rCBF). The infarct volume, plasma high-mobility group box1 (HMGB1) level, and immunoreactivity of the ischemic cerebral cortical tissue (double immunofluorescent labeling) against HMGB1/NeuN (neuron-specific nuclear protein) or HMGB1/MPO (myeloperoxidase) were estimated 24 h after MCAO. ADAMTS13KO mice had larger brain infarcts compared with WT 24 h after MCAO (p < 0.05). The rCBF during reperfusion decreased more in ADAMTS13KO mice. The plasma HMGB1 increased more in ADAMTS13KO mice than in WT after ischemia–reperfusion (p < 0.05). Brain ischemia induced more prominent activation of inflammatory cells co-expressing HMGB1 and MPO and more marked neuronal death in the cortical ischemic penumbra of ADAMTS13KO mice. ADAMTS13 deficiency may enhance systemic and brain inflammation associated with HMGB1 neurotoxicity, and aggravate brain damage in mice after brief focal ischemia. We hypothesize that ADAMTS13 protects brain from ischemia–reperfusion injury by regulating VWF-dependent inflammation as well as microvascular plugging.

Keywords

Brain ischemia–reperfusion High-mobility group box1 ADAMTS13 Inflammation Von Willebrand factor Thrombotic thrombocytopenic purpura 

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Masayuki Fujioka
    • 1
    • 2
    • 3
    • 4
  • Takafumi Nakano
    • 1
  • Kazuhide Hayakawa
    • 1
  • Keiichi Irie
    • 1
    • 5
  • Yoshiharu Akitake
    • 1
    • 5
  • Yuya Sakamoto
    • 1
  • Kenichi Mishima
    • 1
    • 5
  • Carl Muroi
    • 1
    • 5
    • 3
  • Yasuhiro Yonekawa
    • 3
  • Fumiaki Banno
    • 6
  • Koichi Kokame
    • 6
  • Toshiyuki Miyata
    • 6
  • Kenji Nishio
    • 4
  • Kazuo Okuchi
    • 4
  • Katsunori Iwasaki
    • 1
    • 5
  • Michihiro Fujiwara
    • 1
  • Bo K. Siesjö
    • 7
  1. 1.Department of Neuropharmacology, Faculty of Pharmaceutical SciencesFukuoka UniversityFukuokaJapan
  2. 2.Stroke Center, Helios General Hospital AueDresden University of TechnologyDresdenGermany
  3. 3.Department of NeurosurgeryUniversity of ZurichZurichSwitzerland
  4. 4.Emergency and Critical Care Medical CenterNara Medical UniversityNaraJapan
  5. 5.Institute for Aging and Brain SciencesFukuoka UniversityFukuokaJapan
  6. 6.Research Institute, National Cerebral and Cardiovascular CenterSuitaJapan
  7. 7.Laboratory for Experimental Brain ResearchLund UniversityLundSweden

Personalised recommendations