ADAMTS13 reduces VWF-mediated acute inflammation following focal cerebral ischemia in mice
Article first published online: 14 AUG 2012
© 2012 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 10, Issue 8, pages 1665–1671, August 2012
How to Cite
KHAN, M. M., MOTTO, D. G., LENTZ, S. R. and CHAUHAN, A. K. (2012), ADAMTS13 reduces VWF-mediated acute inflammation following focal cerebral ischemia in mice. Journal of Thrombosis and Haemostasis, 10: 1665–1671. doi: 10.1111/j.1538-7836.2012.04822.x
- Issue published online: 14 AUG 2012
- Article first published online: 14 AUG 2012
- Accepted manuscript online: 19 JUN 2012 09:55AM EST
- Received 24 April 2012, accepted 12 June 2012
- cerebral ischemia;
- von Willebrand factor
Summary. Background: ADAMTS13 cleaves hyperactive ultra-large von Willebrand factor (ULVWF) multimers into smaller and less active forms. It remains unknown whether VWF-mediated inflammatory processes play a role in the enhanced brain injury due to ADAMTS13 deficiency.
Objective: We tested the hypothesis that the deleterious effect of ADAMTS13 deficiency on ischemic brain injury is mediated through VWF-dependent enhanced vascular inflammation.
Methods: Transient focal cerebral ischemia was induced by 60 min of occlusion of the right middle cerebral artery. Myeloperoxidase (MPO) activity and inflammatory cytokines in the infarcted region were evaluated 23 h after reperfusion injury. Neutrophil infiltration within the infarct and surrounding areas was quantitated by immunohistochemistry.
Results: We report that ADAMTS13-deficient mice exhibited significantly enlarged infarct size, concordant with increased myeloperoxidase (MPO) activity, neutrophil infiltration and expression of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In contrast, VWF-deficient mice exhibited significantly reduced MPO activity, neutrophil infiltration and inflammatory cytokine induction, demonstrating a role of VWF in these inflammatory processes. Mice deficient for both ADAMTS13 and VWF exhibited an identical reduction of the same inflammatory parameters, demonstrating that the increased inflammation observed in ADAMTS13-deficient mice is VWF dependent. Finally, the increased infarct size observed in ADAMTS13-deficient mice was completely abrogated by prior immunodepletion of neutrophils, demonstrating a causal role for acute inflammation in the enhanced brain injury that occurs in the setting of ADAMTS13 deficiency.
Conclusion: These findings provide new evidence for ADAMTS13 in reducing VWF-mediated acute cerebral inflammation following ischemic stroke.