Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin

Shariat‐Madar, Zia; Mahdi, Fakhri; Warnock, Mark; Homeister, Jonathon W.; Srikanth, Sujata; Krijanovski, Yelena; Murphey, Laine J.; Jaffa, Ayad A.; Schmaier, Alvin H.

doi:10.1182/blood-2006-01-0094

Cited by 81 publications

(110 citation statements)

References 44 publications

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“…Mice deficient for the BK B2 receptor are protected against artificially induced arterial thrombosis, an effect that is probably mediated by the renin-angiotensin system. 45,46 These data provide evidence for an anticoagulation strategy targeting BK and its receptors.…”

Section: Bk Receptorsmentioning

confidence: 92%

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Montfoort

Meijers

2014

Hematology

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The contact pathway of coagulation consists of the proteins factor XI, factor XII, prekallikrein, and high-molecularweight kininogen. Activation of the contact system leads to procoagulant and proinflammatory reactions. The contact system is essential for surface-initiated coagulation, as exemplified by aPTT, but there is probably no role for the contact system in initiating physiologic in vivo coagulation. However, over the last few years, there has been renewed interest, especially because of experimental evidence suggesting that the contact system contributes to thrombosis. Knockout mice deficient in one of the contact proteins were protected against artificially induced thrombosis. Furthermore, inhibiting agents such as monoclonal antibodies, antisense oligonucleotides, and small molecules were found to prevent thrombosis in rodents and primates in both venous and arterial vascular beds. Although it remains to be established whether targeting the contact system will be effective in humans and which of the contact factors is the best target for anticoagulation, it would constitute a promising approach for future effective and safe antithrombotic therapy. Learning Objectives• To understand that the contact system consists of 4 proteins: factor XI, factor XII, PK, and HK • To understand that deficiency of factor XII, PK, or HK is not associated with a bleeding tendency in humans • To understand that targeting the contact system is an effective method to prevent thrombosis in mice •

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Section: Bk Receptorsmentioning

confidence: 92%

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Montfoort

Meijers

2014

Hematology

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“…8,9 Unlike other proteins related to the plasma kallikrein/kinin system (factor XII, high molecular weight kininogen, and the bradykinin B2 receptor), deficiency of PRCP is associated with a prothrombotic state rather than thrombosis protection. 16,30,31 The finding that PRCP gt/gt are hypertensive and it is ameliorated by mitoTEMPO, an antioxidant directed to mitochrondria, suggests that endothelial cell injury may be occurring because of increased ROS. We determined that there is a constitutive increase in uncoupled eNOS and tissue ROS in these animals.…”

Section: Discussionmentioning

confidence: 99%

“…16 The ferric chloride-induced carotid artery damage was performed with a 1 mm ϫ 1 mm filter paper soaked in 4% FeCl 3 and placed on the carotid artery for one minute. In the arterial thrombosis studies, tempol (Enzo Life Sciences) was crushed and placed into a soft dough diet (Transgenic Dough Diet, Bio-Serv) at a dose of 10 mg of drug/gram of food and made fresh daily for 7 days.…”

Section: Arterial Thrombosis Assaysmentioning

confidence: 99%

Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis

Adams¹,

LaRusch²,

Stavrou³

et al. 2011

Blood

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“…39 Interestingly, a previous study suggested that mice lacking the bradykinin receptor B2, which acts downstream of KNG, are protected from thrombosis by increased nitric oxide and prostacyclin formation. 40 Successful prevention of excessive clotting without interfering with physiologic hemostasis would be a major advance in the therapy of many thromboembolic disorders, given that the current drugs used to prevent or reverse thromboembolism are all associated with severe bleeding complications. 41 We have shown that KNG is consumed in the cerebral circulation or tissue after brain ischemia/reperfusion in wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

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

Langhauser¹,

Göb²,

Kraft³

et al. 2012

Blood

116

123

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Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. Highmolecular-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 Ϫ/Ϫ 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 Ϫ/Ϫ 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. (Blood. 2012;120(19): 4082-4092) IntroductionThe pathology of ischemic stroke is complex and involves a myriad of distinct molecular pathways and cellular interactions. Among these, progressive thrombus formation in the cerebral microvasculature is a key process that can cause secondary infarct growth despite successful recanalization of larger proximal brain vessels both under experimental conditions as well as in humans. 1,2 We recently identified the intrinsic coagulation cascade as a novel and safe antithrombotic target for the prevention and treatment of acute ischemic stroke. 3 Genetic depletion or pharmacologic blockade of coagulation factor XII (FXII), the origin of the intrinsic pathway, markedly reduced intracerebral thrombus formation and infarct growth in mice without increasing the risk of bleeding complications. 4,5 Clot formation was also significantly reduced in several in vitro models of thrombosis after FXII inhibition. 5 Current pathophysiologic concepts also emphasize the importance of inflammatory mechanisms in stroke. 6 The cerebral endothelium is activated early during the course of an ischemic event, leading to the up-regulation of cell adhesion molecules and successive trafficking of inflammatory cells (neutrophils, macrophages, T cells) from the blood stream into the brain parenchyma. Those cells attracted from the periphery in concert with resident cell populations (endothelial cells, microglia) secrete an array of soluble immune mediators such as cytokines and chemokines that perpetuate the inflammatory response to cause direct or indirect ti...

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Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin

Cited by 81 publications

References 44 publications

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis

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

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