Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

Friederike Langhauser, Eva Goeb, Peter Kraft, Christian Geis, Joachim Schmitt, Marc Brede, Kerstin Goebel, Xavier Helluy, Mirko Pham, Martin Bendszus, Peter Jakob, Guido Stoll, Sven G. Meuth, Bernhard Nieswandt, Keith R. McCrae, Christoph Kleinschnitz*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

90 Citations (Web of Science)

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.
Original languageEnglish
Pages (from-to)4082-4092
JournalBlood
Volume120
Issue number19
DOIs
Publication statusPublished - 8 Nov 2012

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