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Thomas Renné - One of the best experts on this subject based on the ideXlab platform.
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roles of Factor XII in innate immunity
Frontiers in Immunology, 2019Co-Authors: Thomas Renné, Evi X StavrouAbstract:Factor XII (FXII) is the zymogen of serine protease, Factor XIIa (FXIIa). FXIIa enzymatic activities have been extensively studied and FXIIa inhibition is emerging as a promising target to treat or prevent thrombosis without creating a hemostatic defect. FXII and plasma prekallikrein reciprocally activate each other and result in liberation of bradykinin. Due to its unique structure among coagulation Factors, FXII exerts mitogenic activity in endothelial and smooth muscle cells, indicating that zymogen FXII has activities independent of its protease function. A growing body of evidence has revealed that both FXII and FXIIa upregulate neutrophil functions, contribute to macrophage polarization and induce T-cell differentiation. In vivo, these signaling activities contribute to host defense against pathogens, mediate the development of neuroinflammation, influence wound repair and may facilitate cancer maintenance and progression. Here, we review the roles of FXII in innate immunity as they relate to non-sterile and sterile immune responses.
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Coagulation Factor XII in thrombosis and inflammation.
Blood, 2018Co-Authors: Coen Maas, Thomas RennéAbstract:Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. The Factor XII-driven contact system starts coagulation and inflammatory mechanisms via the intrinsic pathway of coagulation and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. Challenging the concept of the coagulation balance, targeting Factor XII or its activator polyphosphate, provides protection from thromboembolic diseases without interfering with hemostasis. This suggests that the polyphosphate/Factor XII axis contributes to thrombus formation while being dispensable for hemostatic processes. In contrast to deficiency in Factor XII providing safe thromboprotection, excessive FXII activity is associated with the life-threatening inflammatory disorder hereditary angioedema. The current review summarizes recent findings of the polyphosphate/Factor XII-driven contact system at the intersection of procoagulant and proinflammatory disease states. Elucidating the contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory disorders.
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Factor XII-Driven Inflammatory Reactions with Implications for Anaphylaxis.
Frontiers in immunology, 2017Co-Authors: Thomas Renné, Lysann Bender, Henri Weidmann, Stefan Rose-john, Andrew LongAbstract:Anaphylaxis is a life-threatening allergic reaction. It is triggered by the release of pro-inflammatory cytokines and mediators from mast cells and basophils in response to immunologic or non-immunologic mechanisms. Mediators that are released upon mast cell activation include the highly sulfated polysaccharide and inorganic polymer heparin and polyphosphate, respectively. Heparin and polyphosphate supply a negative surface for Factor XII activation, a serine protease that drives contact system-mediated coagulation and inflammation. Activation of the Factor XII substrate plasma kallikrein leads to further activation of zymogen Factor XII and triggers the pro-inflammatory kallikrein-kinin system that results in the release of the mediator bradykinin. The severity of anaphylaxis is correlated with the intensity of contact system activation, the magnitude of mast cell activation, and bradykinin formation. The main inhibitor of the complement system, C1 esterase inhibitor, potently interferes with Factor XII activity, indicating a meaningful crosslink between complement and kallikrein-kinin systems. Deficiency in a functional C1 esterase inhibitor leads to a severe swelling disorder called hereditary angioedema. The significance of Factor XII in these disorders highlights the importance of studying how these processes are integrated and can be therapeutically targeted. In this review, we focus on how Factor XII integrates with inflammation and the complement system to cause anaphylaxis and hereditary angioedema as well as highlight current diagnosis and treatments of bradykinin-related diseases.
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Factor XII contact activation
Seminars in Thrombosis and Hemostasis, 2017Co-Authors: Thomas Renné, Clement Naudin, Elena Burillo, Stefan Blankenberg, Lynn M ButlerAbstract:Contact activation is the surface-induced conversion of Factor XII (FXII) zymogen to the serine protease FXIIa. Blood-circulating FXII binds to negatively charged surfaces and this contact to surfaces triggers a conformational change in the zymogen inducing autoactivation. Several surfaces that have the capacity for initiating FXII contact activation have been identified, including misfolded protein aggregates, collagen, nucleic acids, and platelet and microbial polyphosphate. Activated FXII initiates the proinflammatory kallikrein-kinin system and the intrinsic coagulation pathway, leading to formation of bradykinin and thrombin, respectively. FXII contact activation is well characterized in vitro and provides the mechanistic basis for the diagnostic clotting assay, activated partial thromboplastin time. However, only in the past decade has the critical role of FXII contact activation in pathological thrombosis been appreciated. While defective FXII contact activation provides thromboprotection, excess activation underlies the swelling disorder hereditary angioedema type III. This review provides an overview of the molecular basis of FXII contact activation and FXII contact activation–associated disease states.
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Factor XII as a therapeutic target in thromboembolic and inflammatory diseases
Arteriosclerosis Thrombosis and Vascular Biology, 2017Co-Authors: Katrin F Nickel, Tobias A Fuchs, Lynn M Butler, Andy T Long, Thomas RennéAbstract:Coagulation Factor XII (FXII, Hageman Factor) is a plasma protease that in its active form (FXIIa) initiates the procoagulant and proinflammatory contact system. This name arises from FXII’s unique...
Lynn M Butler - One of the best experts on this subject based on the ideXlab platform.
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Factor XII contact activation
Seminars in Thrombosis and Hemostasis, 2017Co-Authors: Thomas Renné, Clement Naudin, Elena Burillo, Stefan Blankenberg, Lynn M ButlerAbstract:Contact activation is the surface-induced conversion of Factor XII (FXII) zymogen to the serine protease FXIIa. Blood-circulating FXII binds to negatively charged surfaces and this contact to surfaces triggers a conformational change in the zymogen inducing autoactivation. Several surfaces that have the capacity for initiating FXII contact activation have been identified, including misfolded protein aggregates, collagen, nucleic acids, and platelet and microbial polyphosphate. Activated FXII initiates the proinflammatory kallikrein-kinin system and the intrinsic coagulation pathway, leading to formation of bradykinin and thrombin, respectively. FXII contact activation is well characterized in vitro and provides the mechanistic basis for the diagnostic clotting assay, activated partial thromboplastin time. However, only in the past decade has the critical role of FXII contact activation in pathological thrombosis been appreciated. While defective FXII contact activation provides thromboprotection, excess activation underlies the swelling disorder hereditary angioedema type III. This review provides an overview of the molecular basis of FXII contact activation and FXII contact activation–associated disease states.
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Factor XII as a therapeutic target in thromboembolic and inflammatory diseases
Arteriosclerosis Thrombosis and Vascular Biology, 2017Co-Authors: Katrin F Nickel, Tobias A Fuchs, Lynn M Butler, Andy T Long, Thomas RennéAbstract:Coagulation Factor XII (FXII, Hageman Factor) is a plasma protease that in its active form (FXIIa) initiates the procoagulant and proinflammatory contact system. This name arises from FXII’s unique...
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the polyphosphate Factor XII pathway in cancer associated thrombosis novel perspectives for safe anticoagulation in patients with malignancies
Thrombosis Research, 2016Co-Authors: Tobias A Fuchs, Katrin F Nickel, F Langer, Linda Labberton, Lynn M Butler, Andy T Long, Evi X StavrouAbstract:Cancer is an established risk Factor for venous thromboembolism (VTE) and VTE is the second leading cause of death in patients with cancer. The incidence of cancer-related thrombosis is rising and is associated with worse outcomes. Despite our growing understanding on tumor-driven procoagulant mechanisms including cancer-released procoagulant proteases, expression of tissue Factor on cancer cells and derived microvesicles, as well as alterations in the extracellular matrix of the cancer cell milieu, anticoagulation therapy in cancer patients has remained challenging. This review comments on a newly discovered cancer-associated procoagulant pathway. Experimental VTE models in mice and studies on patient cancer material revealed that prostate cancer cells and associated exosomes display the inorganic polymer polyphosphate on their plasma membrane. Polyphosphate activates blood coagulation Factor XII and initiates thrombus formation via the intrinsic pathway of coagulation. Pharmacologic inhibition of Factor XII activity protects mice from VTE and reduces thrombin coagulant activity in plasma of prostate cancer patients. Factor XII inhibitors provide thrombo-protection without impairing hemostatic mechanisms and thus, unlike currently used anticoagulants, do not increase bleeding risk. Interference with the polyphosphate/Factor XII pathway may provide the novel opportunity for safe anticoagulation therapy in patients with malignancies.
Katrin F Nickel - One of the best experts on this subject based on the ideXlab platform.
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Factor XII as a therapeutic target in thromboembolic and inflammatory diseases
Arteriosclerosis Thrombosis and Vascular Biology, 2017Co-Authors: Katrin F Nickel, Tobias A Fuchs, Lynn M Butler, Andy T Long, Thomas RennéAbstract:Coagulation Factor XII (FXII, Hageman Factor) is a plasma protease that in its active form (FXIIa) initiates the procoagulant and proinflammatory contact system. This name arises from FXII’s unique...
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the polyphosphate Factor XII pathway in cancer associated thrombosis novel perspectives for safe anticoagulation in patients with malignancies
Thrombosis Research, 2016Co-Authors: Tobias A Fuchs, Katrin F Nickel, F Langer, Linda Labberton, Lynn M Butler, Andy T Long, Evi X StavrouAbstract:Cancer is an established risk Factor for venous thromboembolism (VTE) and VTE is the second leading cause of death in patients with cancer. The incidence of cancer-related thrombosis is rising and is associated with worse outcomes. Despite our growing understanding on tumor-driven procoagulant mechanisms including cancer-released procoagulant proteases, expression of tissue Factor on cancer cells and derived microvesicles, as well as alterations in the extracellular matrix of the cancer cell milieu, anticoagulation therapy in cancer patients has remained challenging. This review comments on a newly discovered cancer-associated procoagulant pathway. Experimental VTE models in mice and studies on patient cancer material revealed that prostate cancer cells and associated exosomes display the inorganic polymer polyphosphate on their plasma membrane. Polyphosphate activates blood coagulation Factor XII and initiates thrombus formation via the intrinsic pathway of coagulation. Pharmacologic inhibition of Factor XII activity protects mice from VTE and reduces thrombin coagulant activity in plasma of prostate cancer patients. Factor XII inhibitors provide thrombo-protection without impairing hemostatic mechanisms and thus, unlike currently used anticoagulants, do not increase bleeding risk. Interference with the polyphosphate/Factor XII pathway may provide the novel opportunity for safe anticoagulation therapy in patients with malignancies.
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the polyphosphate Factor XII pathway drives coagulation in prostate cancer associated thrombosis
Blood, 2015Co-Authors: Tobias A Fuchs, Carsten Bokemeyer, Katrin F Nickel, Goran Ronquist, F Langer, Linda Labberton, Guido SauterAbstract:Cancer is a leading cause of thrombosis. We identify a new procoagulant mechanism that contributes to thromboembolism in prostate cancer and allows for safe anticoagulation therapy development. Prostate cancer-mediated procoagulant activity was reduced in plasma in the absence of Factor XII or its substrate of the intrinsic coagulation pathway Factor XI. Prostate cancer cells and secreted prostasomes expose long chain polyphosphate on their surface that colocalized with active Factor XII and initiated coagulation in a Factor XII-dependent manner. Polyphosphate content correlated with the procoagulant activity of prostasomes. Inherited deficiency in Factor XI or XII or high-molecular-weight kininogen, but not plasma kallikrein, protected mice from prostasome-induced lethal pulmonary embolism. Targeting polyphosphate or Factor XII conferred resistance to prostate cancer-driven thrombosis in mice, without increasing bleeding. Inhibition of Factor XII with recombinant 3F7 antibody reduced the increased prostasome-mediated procoagulant activity in patient plasma. The data illustrate a critical role for polyphosphate/Factor XII-triggered coagulation in prostate cancer-associated thrombosis with implications for anticoagulation without therapy-associated bleeding in malignancies.
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in vivo activation and functions of the protease Factor XII
Thrombosis and Haemostasis, 2014Co-Authors: Jenny Bjorkqvist, Evi X Stavrou, Katrin F Nickel, Thomas RennéAbstract:Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. Factor XII (FXII, Hageman Factor) is a plasma protease that initiates the contact system. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. The current review concentrates on activators and functions of the FXII-driven contact system in vivo. Elucidating its physiologic activities offers the exciting opportunity to develop strategies for the safe interference with both thrombotic and inflammatory diseases.
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time dependent degradation and tissue Factor addition mask the ability of platelet polyphosphates in activating Factor XII mediated coagulation
Blood, 2013Co-Authors: Katrin F Nickel, Henri M. H. Spronk, Nicola J Mutch, Thomas RennéAbstract:To the editor: Platelets are known to promote coagulation in a Factor XII (FXII)-dependent manner.[1][1] Consistent with earlier studies that identified synthetic platelet-size polyphosphates (polyP) as FXII activators in vitro,[2][2] we have shown that platelet polyP of 60 to 100 phosphate subunit
David Gailani - One of the best experts on this subject based on the ideXlab platform.
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single chain Factor XII a new form of activated Factor XII
Current Opinion in Hematology, 2017Co-Authors: Ivan Ivanov, Anton Matafonov, David GailaniAbstract:Purpose of review Exposure of blood to foreign surfaces induces reciprocal conversion of the plasma proteins Factor XII (fXII) and plasma prekallikrein (PPK) to the proteases α-fXIIa and α-kallikrein. This process, called contact activation, has a range of effects on host defence mechanisms, including promoting coagulation. The nature of the triggering mechanism for contact activation is debated. One hypothesis predicts that fXII has protease activity, either intrinsically or upon surface-binding, that initiates contact activation. We tested this by assessing the proteolytic activity of a recombinant fXII variant that cannot be converted to α-fXIIa. Recent findings The proteolytic activity of fXII-T (for 'triple' mutant), a variant with alanine substitutions for arginine at activation cleavage sites (Arg334, Arg344, and Arg353) was tested with known α-fXIIa substrates. FXII-T activates PPK in solution, and the reaction is enhanced by polyphosphate, an inducer of contact activation released from platelets. In the presence of polyphosphate, fXII-T converts fXII to α-fXIIa, and also converts the coagulation protein Factor XI to its active form. Summary The findings support the hypothesis that contact activation is initiated through activity intrinsic to single-chain fXII, and indicate that preexisting α-fXIIa is not required for induction of contact activation.
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Factor XII promotes blood coagulation independent of Factor xi in the presence of long chain polyphosphates
Journal of Thrombosis and Haemostasis, 2013Co-Authors: Cristina Puy, David Gailani, Andras Gruber, Erik I. Tucker, Sharon H Choi, Stephanie A Smith, James H Morrissey, Zoe C Wong, Owen J. T. MccartyAbstract:Background Inorganic polyphosphates (polyP), which are secreted by activated platelets (short chain polyP) and accumulate in some bacteria (long chain polyP), support the contact activation of Factor XII (FXII), and accelerate the activation of Factor XI (FXI).
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Factor xi contributes to thrombin generation in the absence of Factor XII
Blood, 2008Co-Authors: Dmitri V Kravtsov, Peter N. Walsh, Maofu Sun, Andras Gruber, Erik I. Tucker, Anton Matafonov, David GailaniAbstract:During surface-initiated blood coagulation in vitro, activated Factor XII (fXIIa) converts Factor XI (fXI) to fXIa. Whereas fXI deficiency is associated with a hemorrhagic disorder, Factor XII deficiency is not, suggesting that fXI can be activated by other mechanisms in vivo. Thrombin activates fXI, and several studies suggest that fXI promotes coagulation independent of fXII. However, a recent study failed to find evidence for fXII-independent activation of fXI in plasma. Using plasma in which fXII is either inhibited or absent, we show that fXI contributes to plasma thrombin generation when coagulation is initiated with low concentrations of tissue Factor, Factor Xa, or α-thrombin. The results could not be accounted for by fXIa contamination of the plasma systems. Replacing fXI with recombinant fXI that activates Factor IX poorly, or fXI that is activated poorly by thrombin, reduced thrombin generation. An antibody that blocks fXIa activation of Factor IX reduced thrombin generation; however, an antibody that specifically interferes with fXI activation by fXIIa did not. The results support a model in which fXI is activated by thrombin or another protease generated early in coagulation, with the resulting fXIa contributing to sustained thrombin generation through activation of Factor IX.
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role of Factor XII in hemostasis and thrombosis clinical implications
Expert Review of Cardiovascular Therapy, 2007Co-Authors: Thomas Renné, David GailaniAbstract:The plasma coagulation system reacts quickly to limit blood loss from injury sites but also contributes to vascular thrombosis. In current models of hemostatic balance, normal coagulation and thrombosis represent two sides of the same coin, however, recent data from gene-deleted murine models have challenged this dogma. Deficiency of coagulation Factor XII (Hageman Factor), a serine protease that initiates the intrinsic pathway of coagulation, severely impairs arterial thrombus formation but is not associated with excessive bleeding. These findings suggest that fibrin-generating mechanisms that operate during pathologic thrombus formation involve pathways distinct from those that are active during normal hemostasis. As Factor XII selectively contributes to thrombus formation in occlusive disease, but not to normal hemostasis, inhibition of this protease may offer a novel treatment strategy for prevention of arterial thrombosis with minimal or no risk of bleeding.
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defective thrombus formation in mice lacking coagulation Factor XII
Journal of Experimental Medicine, 2005Co-Authors: Thomas Renné, David Gailani, Kai Schuh, H U Pauer, Peter Burfeind, Miroslava Pozgajova, Sabine Gruner, Bernhard NieswandtAbstract:Blood coagulation is thought to be initiated by plasma protease Factor VIIa in complex with the membrane protein tissue Factor. In contrast, coagulation Factor XII (FXII)–mediated fibrin formation is not believed to play an important role for coagulation in vivo. We used FXII-deficient mice to study the contributions of FXII to thrombus formation in vivo. Intravital fluorescence microscopy and blood flow measurements in three distinct arterial beds revealed a severe defect in the formation and stabilization of platelet-rich occlusive thrombi. Although FXII-deficient mice do not experience spontaneous or excessive injury-related bleeding, they are protected against collagen- and epinephrine-induced thromboembolism. Infusion of human FXII into FXII-null mice restored injury-induced thrombus formation. These unexpected findings change the long-standing concept that the FXII-induced intrinsic coagulation pathway is not important for clotting in vivo. The results establish FXII as essential for thrombus formation, and identify FXII as a novel target for antithrombotic therapy.
Kusumam Joseph - One of the best experts on this subject based on the ideXlab platform.
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Factor XII independent activation of the bradykinin forming cascade implications for the pathogenesis of hereditary angioedema types i and ii
The Journal of Allergy and Clinical Immunology, 2013Co-Authors: Kusumam Joseph, Baby G Tholanikunnel, Anette Bygum, Berhane GhebrehiwetAbstract:Background We have previously reported that prekallikrein expresses an active site when it is bound to high-molecular-weight kininogen (HK) and can digest HK to produce bradykinin. The reaction is stoichiometric and inhibited by C1 inhibitor (C1-INH) or corn trypsin inhibitor. Addition of heat shock protein 90 leads to conversion of prekallikrein to kallikrein in a zinc-dependent reaction. Objective Our goal was to determine whether these reactions are demonstrable in plasma and distinguish them from activation through Factor XII. Methods Plasma was incubated in polystyrene plates and assayed for kallikrein formation. C1-INH was removed from Factor XII–deficient plasma by means of immunoadsorption. Results We demonstrate that prekallikrein-HK will activate to kallikrein in phosphate-containing buffers and that the rate is further accelerated on addition of heat shock protein 90. Prolonged incubation of plasma deficient in both Factor XII and C1-INH led to conversion of prekallikrein to kallikrein and cleavage of HK, as was seen in plasma from patients with hereditary angioedema but not plasma from healthy subjects. Conclusions These results indicate that C1-INH stabilizes the prekallikrein-HK complex to prevent HK cleavage either by prekallikrein or by prekallikrein-HK autoactivation to generate kallikrein. In patients with hereditary angioedema, kallikrein and bradykinin formation can occur without invoking Factor XII activation, although the kallikrein formed can rapidly activate Factor XII if it is surface bound.
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Factor XII independent cleavage of high molecular weight kininogen by prekallikrein and inhibition by c1 inhibitor
The Journal of Allergy and Clinical Immunology, 2009Co-Authors: Kusumam Joseph, Baby G Tholanikunnel, Allen P KaplanAbstract:Background Bradykinin formation typically requires interaction of Factor XII, prekallikrein (PK), and high-molecular-weight kininogen (HK) with negatively charged exogenous initiators or cell-surface proteins. Approximately 85% of plasma PK circulates as a complex with HK. Nonenzymatic cell-derived initiators, such as heat shock protein 90, can activate the HK-PK complex to generate kallikrein, bradykinin, and cleaved HK, even in the absence of Factor XII. Objective We sought to determine whether PK, without activation to kallikrein, can digest HK to release bradykinin. Methods Kallikrein was measured by using a chromogenic assay, and bradykinin levels were determined by ELISA. Cleavage of PK and HK were assessed by SDS-PAGE and Western blot analysis. Results Cleavage of HK by PK is demonstrated without any conversion of PK to kallikrein. HK cleavage by PK is distinguished from that of kallikrein by the following: (1) stoichiometric activation of HK by PK with release of bradykinin proportional to the PK input; (2) inhibition of PK cleavage of HK by corn trypsin inhibitor, which has no effect on kallikrein; and (3) inhibition of PK cleavage of HK by a peptide derived from HK, which inhibits binding of PK to HK. The same peptide has no effect on kallikrein activation of HK. C1 inhibitor (C1INH), the major control protein of the plasma bradykinin-forming cascade, inhibits PK cleavage of HK. Conclusion PK is an enzyme that can cleave HK to release bradykinin, and this reaction is inhibited by C1INH. This might account, in part, for circulating bradykinin levels and initiation of kinin formation in C1INH deficiency.
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heat shock protein 90 catalyzes activation of the prekallikrein kininogen complex in the absence of Factor XII
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Kusumam Joseph, Baby G Tholanikunnel, Allen P KaplanAbstract:Bradykinin is a major mediator of swelling in C1 inhibitor deficiency as well as the angioedema seen with ACE inhibitors and may contribute to bronchial hyperreactivity in asthma. Formation of bradykinin occurs in the fluid phase and along cell surfaces requiring interaction of Factor XII, prekallikrein, and high Mr kininogen (HK). Recent data suggest that activation of the kinin-forming cascade can occur on the surface of endothelial cells, even in the absence of Factor XII. We sought to further define this Factor XII-independent mechanism of kinin formation. Both cytosolic and membrane fractions from endothelial cells possessed the ability to catalyze prekallikrein conversion to kallikrein, and activation depended on the presence of HK and zinc ion. We fractionated the cytosol by ion exchange chromatography and affinity chromatography by using corn trypsin inhibitor as ligand. The fractions with peak activity were subjected to SDS gel electrophoresis and ligand blot with biotinylated corn trypsin inhibitor, and positive bands were sequenced. Heat shock protein 90 (Hsp90) was identified as the protein responsible for zinc-dependent prekallikrein activation in the presence of HK. Zinc-dependent activation of the prekallikrein-HK complex also depended on addition of either α and β isoforms of Hsp90 and the activation on endothelial cells was inhibited on addition of polyclonal Ab to Hsp90 in a dose-dependent manner. Although the mechanism by which Hsp90 activates the kinin-forming cascade is not understood, this protein represents the cellular contribution to the reaction and may become the dominant mechanism in pathologic circumstances in which Hsp90 is highly expressed or secreted.
