Kininogen Deficiency Protects From Ischemic Neurodegeneration in Mice by Reducing Thrombosis, Blood-Brain-Barrier Damage and Inflammation

High molecular weight kininogen (HK) is an abundant plasma protein that serves as an important component of the intrinsic pathway of coagulation. Recent studies have suggested an important role for the intrinsic coagulation pathway in pathologic thrombosis. We have previously described the production of kininogen deficient mice (Kng1−/−), and the prolongation of Rose-Bengal induced carotid artery occlusion in these animals with no effect on the bleeding time. Kininogen also plays a central role in enhancing vascular permeability through the release of the nonapeptide bradykinin following cleavage by plasma kallikrein, and has been implicated in mediating acute inflammatory responses. Since thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions, we hypothesized that the severity of acute ischemic stroke would be ameliorated in kininogen deficient mice.

We investigated the consequences of kininogen deficiency in models of ischemic stroke. Kng−/− mice of either sex subjected to transient middle cerebral artery occlusion (tMCAO) developed dramatically smaller brain infarctions and less severe neurological deficits without an increase in infarct associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice, but was lost after replacement of exogenous kininogen in the deficient mice. The improved outcomes were attributable to markedly reduced thrombus formation in ischemic vessels of mKng1−/− mice, improved cerebral blood flow, and less severe blood-brain barrier damage and edema formation. Moreover, the ingress of inflammatory cells (monocytes and neutrophils), and levels of IL-1 were significantly decreased in the absence of kininogen, consistent with a reduced inflammatory response following ischemic injury. The survival of mice subjected to tMCAO was markedly improved compared to control animals.

Mice deficient in kininogen were markedly protected from acute ischemic stroke in the transient middle cerebral artery occlusion model. Protection was mediated through decreased thrombus formation, diminished vascular permeability, and a dampened inflammatory response. The mechanisms underlying these altered responses are currently under investigation. However, since kininogen appears to be instrumental in pathologic thrombus formation and inflammation, but entirely dispensable for normal hemostasis, kininogen inhibition may offer a safe and selective strategy for combating the effects of stroke and other thromboembolic diseases.

No relevant conflicts of interest to declare.