title: Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation.
abstract: Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. High-molecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng(-/-) mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng(-/-) mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases.
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Langhauser
authors.forename: Eva
authors.initials: E
authors.lastname: Göb
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Christian
authors.initials: C
authors.lastname: Geis
authors.forename: Joachim
authors.initials: J
authors.lastname: Schmitt
authors.forename: Marc
authors.initials: M
authors.lastname: Brede
authors.forename: Kerstin
authors.initials: K
authors.lastname: Göbel
authors.forename: Xavier
authors.initials: X
authors.lastname: Helluy
authors.forename: Mirko
authors.initials: M
authors.lastname: Pham
authors.forename: Martin
authors.initials: M
authors.lastname: Bendszus
authors.forename: Peter
authors.initials: P
authors.lastname: Jakob
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Keith R
authors.initials: KR
authors.lastname: McCrae
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000098:blood supply / Q000473:pathology; D001929:Brain Edema / Q000235:genetics / Q000517:prevention & control; D002545:Brain Ischemia / Q000235:genetics / Q000401:mortality / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D020300:Intracranial Hemorrhages / Q000175:diagnosis; D007704:Kininogens / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012039:Regional Blood Flow; D020521:Stroke / Q000235:genetics / Q000401:mortality / Q000517:prevention & control; D013927:Thrombosis / Q000235:genetics / Q000503:physiopathology*
chemical_list: D007704:Kininogens