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.