title: von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke.
abstract: Stroke is a leading cause of death and disability. The only therapy available is recombinant tissue plasminogen activator, but side effects limit its use. Platelets play a crucial role during stroke, and the inflammatory reaction promotes neurodegeneration. von Willebrand factor (VWF), an adhesion molecule for platelets, is elevated in patients with acute stroke. The activity of VWF is modulated by ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) that cleaves VWF to smaller less-active forms. We recently documented that ADAMTS13 negatively regulates both thrombosis and inflammation. We report that deficiency or reduction of VWF reduces infarct volume up to 2-fold after focal cerebral ischemia in mice, thus showing the importance of VWF in stroke injury. In contrast, ADAMTS13 deficiency results in larger infarctions, but only in mice that have VWF. Importantly, infusion of a high dose of recombinant human ADAMTS13 into a wild-type mouse immediately before reperfusion reduces infarct volume and improves functional outcome without producing cerebral hemorrhage. Furthermore, recombinant ADAMTS13 did not enhance bleeding in a hemorrhagic stroke model. Our findings show the importance of VWF in regulating infarction and suggest that recombinant ADAMTS13 could be considered as a new therapeutic agent for prevention and/or treatment of stroke.
authors.affiliation: Immune Disease Institute, Boston, MA 02115, USA.
authors.forename: Bing-Qiao
authors.initials: BQ
authors.lastname: Zhao
authors.forename: Anil K
authors.initials: AK
authors.lastname: Chauhan
authors.forename: Matthias
authors.initials: M
authors.lastname: Canault
authors.forename: Ian S
authors.initials: IS
authors.lastname: Patten
authors.forename: Janie J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Dockal
authors.forename: Friedrich
authors.initials: F
authors.lastname: Scheiflinger
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D051722:ADAM Proteins / Q000494:pharmacology*; D000071120:ADAMTS13 Protein; D000818:Animals; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000494:pharmacology; D020521:Stroke / Q000201:enzymology* / Q000517:prevention & control*; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D014841:von Willebrand Factor; D051722:ADAM Proteins; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
references.citation: Blood. 2009 Apr 9;113(15):3600-3
references.pmid: 19182208
references.citation: J Exp Med. 2006 Mar 20;203(3):767-76
references.pmid: 16533881
references.citation: Nat Med. 2006 Nov;12(11):1278-85
references.pmid: 17072311
references.citation: Eur J Pediatr. 2007 Mar;166(3):249-57
references.pmid: 17187257
references.citation: Thromb Haemost. 1999 Aug;82(2):938-46
references.pmid: 10605807
references.citation: Blood. 2008 Apr 1;111(7):3452-7
references.pmid: 18083848
references.citation: Circulation. 2007 May 1;115(17):2323-30
references.pmid: 17438148
references.citation: J Thromb Haemost. 2003 Jul;1(7):1335-42
references.pmid: 12871266
references.citation: Nat Med. 2006 Apr;12(4):441-5
references.pmid: 16565723
references.citation: J Clin Invest. 2005 Oct;115(10):2752-61
references.pmid: 16200209
references.citation: Blood. 2008 May 15;111(10):4958-64
references.pmid: 18256319
references.citation: Platelets. 1998;9(3-4):155-9
references.pmid: 16793694
references.citation: Stroke. 2006 Nov;37(11):2672-7
references.pmid: 16990571
references.citation: J Clin Invest. 2000 Aug;106(3):385-92
references.pmid: 10930441
references.citation: J Thromb Haemost. 2006 Jun;4(6):1186-93
references.pmid: 16706957
references.citation: N Engl J Med. 1998 Nov 26;339(22):1585-94
references.pmid: 9828246
references.citation: Blood. 2006 Dec 1;108(12):3746-52
references.pmid: 16926295
references.citation: Nat Med. 2003 Aug;9(8):1020-5
references.pmid: 12858167
references.citation: Br J Haematol. 2005 Apr;129(1):93-100
references.pmid: 15801961
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9524-9
references.pmid: 9689113
references.citation: J Exp Med. 2008 Sep 1;205(9):2065-74
references.pmid: 18695007
references.citation: J Biochem. 2006 Jan;139(1):147-54
references.pmid: 16428330
references.citation: J Clin Invest. 1998 Oct 1;102(7):1301-10
references.pmid: 9769322
references.citation: J Cereb Blood Flow Metab. 2006 May;26(5):654-65
references.pmid: 16121126
references.citation: Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):728-39
references.pmid: 17272754
references.citation: Blood. 1999 Jun 15;93(12):4277-83
references.pmid: 10361125
references.citation: Annu Rev Cell Biol. 1990;6:217-46
references.pmid: 2275814
references.citation: Neurology. 1999;53(7 Suppl 4):S3-14
references.pmid: 10532643
references.citation: N Engl J Med. 1998 Nov 26;339(22):1578-84
references.pmid: 9828245
references.citation: Annu Rev Med. 2005;56:173-91
references.pmid: 15660508
references.citation: J Clin Invest. 1996 Jan 15;97(2):493-500
references.pmid: 8567972
references.citation: Blood. 2008 Jul 1;112(1):11-8
references.pmid: 18574040
references.citation: Exp Neurol. 2007 Feb;203(2):555-67
references.pmid: 17067578