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

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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.

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Authors and Affiliations

  1. Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan

    Masayuki Fujioka, Takafumi Nakano, Kazuhide Hayakawa, Keiichi Irie, Yoshiharu Akitake, Yuya Sakamoto, Kenichi Mishima, Carl Muroi, Katsunori Iwasaki & Michihiro Fujiwara

  2. Stroke Center, Helios General Hospital Aue, Dresden University of Technology, Dresden, Saxony, Germany

    Masayuki Fujioka

  3. Department of Neurosurgery, University of Zurich, Zurich, Switzerland

    Masayuki Fujioka, Carl Muroi & Yasuhiro Yonekawa

  4. Emergency and Critical Care Medical Center, Nara Medical University, Nara, Japan

    Masayuki Fujioka, Kenji Nishio & Kazuo Okuchi

  5. Institute for Aging and Brain Sciences, Fukuoka University, Fukuoka, Japan

    Keiichi Irie, Yoshiharu Akitake, Kenichi Mishima, Carl Muroi & Katsunori Iwasaki

  6. Research Institute, National Cerebral and Cardiovascular Center, Suita, Japan

    Fumiaki Banno, Koichi Kokame & Toshiyuki Miyata

  7. Laboratory for Experimental Brain Research, Lund University, Lund, Sweden

    Bo K. Siesjö

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  1. Masayuki Fujioka
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  2. Takafumi Nakano
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Correspondence to Masayuki Fujioka.

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Fujioka, M., Nakano, T., Hayakawa, K. et al. ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia–reperfusion injury. Neurol Sci 33, 1107–1115 (2012). https://doi.org/10.1007/s10072-011-0913-9

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