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The plasma kallikrein kinin system its evolution from contact activation
 

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    The plasma kallikrein kinin system its evolution from contact activation The plasma kallikrein kinin system its evolution from contact activation Document Transcript

    • Journal of Thrombosis and Haemostasis, 5: 2323–2329 REVIEW ARTICLE The plasma kallikrein–kinin system: its evolution from contact activation A . H . S C H M A I E R and K . R . M C C R A E Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH, USA To cite this article: Schmaier AH, McCrae KR. The plasma kallikrein–kinin system: its evolution from contact activation. J Thromb Haemost 2007; 5: 2323–9. review will outline physiologic activities of the plasma KKS Summary. The plasma kallikrein–kinin system consists of the that are not emphasized in other recent reviews [1,2]. proteins factor XII (FXII), prekallikrein (PK), and high FXII deficiency (Hageman trait) was discovered by Ratnoff molecular weight kininogen. It was first recognized as a sur- and Colopy in an individual who had prolonged blood clotting face-activated coagulation system that is activated when blood times without bleeding [3]. Activation of FXII results in FXI or plasma interacts with artificial surfaces. Although surface- activation, giving rise to the coagulation cascade [4]. As result activated contact activation occurs in vivo in the case of tissue of elucidating non-FXII-deficient etiologies for isolated pro- destruction or a developing thrombus, the physiologic basis for longed activated partial thromboplastin times (APTT), plasma the activation and function of this system has not been PK and HK were discovered [5,6]. These proteins influence the delineated. New investigations indicate that there is a proteo-  200 million surface-activated coagulation tests, APTTs and lytic pathway on cells for PK activation independent of FXII. activated clotting times performed annually in the USA. New This pathway for PK with subsequent FXII activation indicates interest in FXII has arisen since it has been observed that FXII- physiologic activities. These activities include blood pressure deficient mice have reduced thrombus compared to the wild regulation and modulation of thrombosis risk independently of type [7]. Furthermore, bradykinin (BK) B2 receptor (B2R)- hemostasis. Furthermore, they include regulation of endothelial deficient mice also have reduced thrombosis risk [8]. C1 esterase cell proliferation, angiogenesis and apoptosis through a cellular- inhibitor (C1INH), the SERPIN inhibitor of the enzymes of based, outside-in signaling system. The present characteriza- this system, accounts for 90% of inhibition of FXIIa and 50% tions of this system, which incorrectly had been thought to of inhibition of plasma kallikrein [9,10] (Table 2). Although initiate coagulation, represent an evolution of understanding in plasminogen activator inhibitor-1 and protein C inhibitor, this field. mole for mole, may be more potent inhibitors of plasma kallikrein than C1INH, the intravascular concentration of Introduction C1INH is highest, making it the most important (Table 2). C1INH deficiency is the etiology of hereditary angioedema, a Appreciation of the plasma kallikrein–kinin system (KKS) has disorder associated with unregulated BK formation, producing grown. The KKS consists of two zymogens, factor XII (FXII) secondary angioedema in humans and mice [11]. and prekallikrein (PK), and one substrate/cofactor, high molecular weight kininogen (HK) (Table 1). These proteins influence surface-activated in vitro coagulation assays, but Contact activation of FXII and the proteins of the plasma deficiencies are not associated with bleeding. Recent studies KKS indicate activities in vascular biology, including modulation of The three proteins (FXII, PK, and HK) of the plasma KKS are thrombosis risk independently of blood coagulation. This called Ôcontact factorsÕ because, until recently (see next section), there was no known mechanism for their initiation of activation other than FXII autoactivation on surfaces [2,3]. Autoactiva- Correspondence: Alvin H. Schmaier, Case Western Reserve tion is the event where zymogen FXII becomes an enzyme in the University, University Hospital Case Medical Center, Division of presence of a negatively charged surface, a process twentynine- Hematology and Oncology, 10900 Euclid Avenue WRB2-130, Cleveland, OH 44106-7284, USA. fold less efficient than activation by plasma kallikrein [12] Tel.: +1 216 368 1172; fax: +1 216 368 3014; e-mail: (Table 1). The biochemistry of this phenomenon is not under- schmaier@case.edu stood, but recent studies using sum frequency generation vibrational spectroscopy indicate that FXII autoactivation at Received 3 August 2007, accepted 14 September 2007 the molecular level occurs by imposing specific orientation and Ó 2007 International Society on Thrombosis and Haemostasis
    • 2324 A. H. Schmaier and K. R. McCrae Table 1 Enzymes/substrates of the plasma kallikrein–kinin system Enzyme Substrate Kinetics Reference a-Factor (F) XIIa Prekallikrein 1.8 lM Km; kcat/Km = 0.57 lM [87] FXI – [88] Complement C1 – [89] FVII – [90] Plasminogen – [91] High-Mr kininogen – [89] b-FXIIa Prekallikrein 2.1 lM Km; kcat/Km = 1.67 lM [87] Autoactivation of FXII FXII 2.4 lM Km; kcat/Km = 0.02 lM [92] Plasma kallikrein FXII 11 lM Km; kcat/Km = 0.57 lM [88] Single-chain urokinase 0.064 lM Km [22] High-Mr kininogen 1.4 lM Km; kcat/Km = 0.46 lM [93] Prolylcarboxypeptidase Prekallikrein 0.007 lM Km [35] Table 2 Inhibitors of the enzymes of the plasma kallikrein–kinin system independently of HK [22–24]. FXI also binds to prothrombin Enzyme Inhibitor Inhibition constant+ Reference and the glycoprotein Iba–IX–V complex on platelets [24,25]. Membrane-binding proteins of HK include gC1qR, urokinase a-Factor C1 inhibitor 222.0 · 103 M)1 min)1 [9] plasminogen activator receptor (u-PAR), and cytokeratin 1 (F) XIIa a2-Antiplasmin 11.0 · 103 M)1 min)1 [9] (CK1) (Fig. 1) [26–29]. When HK is proteolyzed by plasma a2-Macroglobulin 5.3 · 103 M)1 min)1 [9] Antithrombin 1.3 · 103 M)1 min)1 [9] kallikrein or other proteases to form cleaved HK (HKa), Plasma C1 inhibitor 102.0 · 104 M)1 min)1 [9] membrane tropomysin also functions as a binding site uniquely kallikrein a2-Macroglobulin 69.0 · 104 M)1 min)1 [10] for this form of kininogen [30]. FXII also has been shown to Antithrombin 1.8 · 104 M)1 min)1 [10] bind to gC1qR, u-PAR, and CK1 [27,31]. Both PK and FXI a1-Antitrypsin 0.025 · 104 M)1 min)1 [10] circulate in plasma almost completely bound to HK, but PK PAI-1 360.0 · 104 M)1 min)1 [94] Protein C inhibitor 600.0 · 104 M)1 min)1 [95] binding to endothelial cells predominates [24]. The reasons for this are as follows: (i) the concentration of PK (450 nM) is more PAI-1, plasminogen activator inhibitor-1. + than tenfold greater than that of FXI (30 nM) in plasma; and The values are second-order rate constants. (ii) the free Zn2+ concentration required for PK binding is only 0.3 lM, whereas that for FXI binding is 7 lM [24]. ordering of the adsorbed protein molecules that lead to When HK and PK assemble on endothelial cells and matrix, expression of its active site [13]. Negatively charged surfaces plasma kallikrein activity arises independently of added FXIIa. consist of artificial materials as found in coagulation assays such This event occurs in the presence of neutralizing antibody to as kaolin, celite, and glass surfaces. Several physiologic substances, such as articular cartilage, skin, fatty acids, endo- toxin, sodium urate crystals, calcium pyrophosphate, L-homo- cysteine, hematin, protoporphyrin, sulfatides, heparins, chondrotin sulfates, and amyloid b-protein, also support autoactivation of FXII. Formation of activated FXII by autoactivation results in PK activation with reciprocal activa- tion of FXII and PK and activation amplification of the system. In vivo, FXII autoactivation occurs on developing thrombus, contributing to its extent [7]. Substances that contribute to Ôcontact activationÕ on a developing thrombus include RNA from degrading cells, polysomes from platelet membranes, and fibrin itself [14,15]. FXII activation also occurs under conditions of sepsis, where bacteria provide a negatively charged surface, proteases to activate FXII, or a binding site [16,17]. Fig. 1. Physiologic assembly and activation of the plasma kallikrein–kinin system. The high molecular weight kininogen (HK)–prekallikrein (PK) Constitutive activation of the plasma KKS in the complex binds to its HUVEC receptor complex, which includes cytoker- atin 1 (CK1), urokinase plasminogen activator receptor (u-PAR) and intravascular compartment gC1qR. Prolylcarboxypeptidase (PRCP) bound to the complex activates It has been recognized that HK, FXII and PK specifically, PK to form plasma kallikrein (KAL). The KAL cleaves HK and acti- vates FXII and single-chain urokinase plasminogen activator (Scu-PA). saturably and reversibly bind to endothelial cells, platelets Cleaved HK liberates bradykinin (BK), which is a potent activator of and granulocytes [18–21]. HK serves as the major binding site tissue-type plasminogen activator (t-PA), NO (nitric oxide) and prosta- for PK and FXI, although both bind to endothelial cells cyclin (PGI2) liberation from endothelial cells. HKa, cleaved HK. Ó 2007 International Society on Thrombosis and Haemostasis
    • The changing kallikrein–kinin system 2325 FXII and FXII-deficient plasma, but not PK-deficient plasma Vascular activities of the plasma KKS [22,32]. The plasma kallikrein formed results in kinetically favorable single-chain urokinase activation (Km = 64 nM) Regulation of blood pressure and flow Local BK formation (Table 1) [22]. The plasma kallikrein on endothelial cells also is known to influence blood pressure. BK is liberated from HK results in kinetically favorable FXII activation [33]. These data by plasma or tissue kallikrein cleavage. The nine amino acid provide an alternative hypothesis to contact activation for BK peptide, RPPGFSPFR, has two intravascular receptors: FXIIa formation in vivo. The increased requirements for free B2R, which is constitutively expressed, and the BK B1 receptor Zn2+ for FXII binding to endothelial cells suggest that FXIIÕs (B1R), which becomes expressed in inflammatory states. BK association and activation on endothelial cells follows HK and binds to B2R, a seven-transmembrane G-protein-coupled PK assembly and activation [24,31]. This proposed mechanism receptor, and stimulates its G-proteins to release nitric oxide for PK activation in vivo may be occurring constitutively. (NO), prostaglandin I2 (prostacyclin), smooth muscle Firstly, C1INH knockout mice have constitutive tissue edema hyperpolarization factor, and superoxide [43–46]. In sepsis, due to increased BK, as it is blocked by a B2R antagonist or by excessive BK release contributes to hypotension. mating C1INH and B2R knockout mice [11]. As plasma BK BK produced by the plasma and tissue KKS influences only arises from plasma kallikrein formation and C1INH only cardiovascular physiology. B2R knockout mice are not consti- inhibits plasma kallikrein, not tissue kallikein, BK must be tutively hypertensive; however, upon being subjected to a salt constantly formed in vivo to give the paw edema seen [11]. load, they have early-onset salt-sensitive hypertension [47]. B2R Secondly, FXII knockout mice also have plasma BK formation is involved in the control of regional vascular tone in the coro- without the presence of FXII [34]. nary arteries and the kidneys. The cardioprotective effects of A PK activator was purified from endothelial cells [35]. On angiotensin-converting enzyme (ACE) inhibition, which inhibits amino acid sequencing, it was identified as the serine protease BK degradation, is lost in B2R knockout mice. In diabetic mice, prolylcarboxypeptidase (PRCP) [35]. The Km of PRCP activa- the absence of B2R increases oxidative stress, mitochondrial tion of plasma PK (Km = 7 nM) is two hundred and fifty- to DNA damage, and senescence-associated phenotypes [48]. In three hundredfold higher than that for activated forms of FXII tissue kallikrein knockout mice, with reduced tissue BK (Table 1). This suggests that PRCP activation of PK is favored formation, there is thinning of the septum and posterior wall over that of a-FXIIa or b-FXIIa in vivo (Table 1). It is of note of the heart, resulting in ventricular dilatation and reduced left that C1INH is a tighter inhibitor of plasma kallikrein than of ventricular mass [49]. Furthermore, genetic kininogen deficiency activated FXII, suggesting that plasma kallikrein regulation is in rats contributes to aortic aneurysm formation [50]. more important than that of FXIIa (Table 2). PRCP was first recognized as a degrading enzyme for BK and angiotensin II Thrombosis risk Emerging information indicates that the (Ki  1 and 0.15 mM, respectively) by cleaving Pro-X bonds on plasma KKS influences thrombosis risk independently of the C-terminus of the protein [36]. Both purified and hemostasis [7,8]. Patients with FXII, PK and HK deficiency are recombinant PRCP activate PK with a Km  7–17 nM exceedingly rare, and although they do not bleed, there are too [35,37]. Although thought to be lysosomal in origin, PRCP is few patients to characterize a common clinical phenotype. a membrane and matrix protein, as it can be demonstrated to be FXII deficiency is more common than HK or PK deficiency. there functionally and immunochemically and it was interrupted Clinical investigations for venous thrombosis risk or on by a gene trap targeted to membrane proteins [35,37–39]. PRCP polymorphisms of FXII and their influence on cardiovascular is a risk factor for metabolic syndrome in men, and a PRCP disease have been conflicting (see below). The clearest polymorphism is associated with pre-eclampsia in women information on thrombosis risk or risk amelioration has been [40,41]. CHO cells with overexpressed PRCP have increased derived from animal models, which demonstrate unexpected PK-activating activity over controls; treatment of these cells findings. with small interfering RNA reduces the PK activation on these cells [42]. Finally, transfected CHO cells mostly express PRCP BK and kininogen BK infusion is a potent stimulant for tissue- on their membranes. These combined studies indicate that there type plasminogen activator (t-PA) release in rabbits and humans is a constitutive, physiologic endothelial cell mechanism for PK [51]. Kininogen itself has been shown to have antithrombin activation independent of FXII autoactivation by contact. activities. Both HK and low molecular weight kininogen at 5% of their physiologic concentrations block thrombin-induced platelet aggregation and serotonin release by inhibiting Activities of the plasma KKS thrombin binding to platelets [52]. The thrombin inhibitory The studies described above reveal a means for KKS assembly regions of kininogen have been associated with domains 3 and 4, and activation by physiologic and pathophysiologic mecha- the BK region [53,54]. A peptide comprising the first five amino nisms. Several vascular and cellular activities derive from these acids of BK, RPPGF, was found to bind weakly to the active site pathways. KKS vascular activities include regulation of blood of thrombin upon cocrystallization, and to bind the exodomains pressure and flow and thrombosis risk; the cellular activities of protease-activated receptor (PAR)1 and PAR4 to prevent include cellular proliferation, growth, angiogenesis, apoptosis, thrombin cleavage [55,56]. RPPGF inhibits in vitro and, when and inflammation. infused in dogs and humans, ex vivo thrombin-induced platelet Ó 2007 International Society on Thrombosis and Haemostasis
    • 2326 A. H. Schmaier and K. R. McCrae aggregation [57,58]. RPPGF in pharmacologic doses prevents binds to the overexpressed angiotensin receptor 2 to increase carotid artery thrombosis in mice and coronary artery NO and prostacyclin, and prolong the bleeding time of the thrombosis in dogs [57,59,60]. animal [8] (Fig. 2). Thirdly, RPPGF is elevated in these animals, As BK induces NO, prostacyclin and t-PA release from due to increased BK degradation by ACE [8]. The elevation of endothelial cells, we hypothesized that the B2R knockout mouse RPPGF levels may also contribute to the thrombosis protection. would be prothrombotic. To our surprise, B2R knockout mice These combined studies indicate that BK and its receptor system have delayed carotid artery occlusion times in the Rose Bengal indirectly influence thrombosis risk by influencing endothelial model (Fig. 2) [8]. The mechanism for thrombosis protection is cell biology through cross-talk with components of the plasma dependent on this systemÕs interaction with the renin–angioten- RAS. Such a pathway for risk modification of intra-arterial sin system (RAS) [61]. In the RAS, angiotensinogen is converted thrombosis has not been previously appreciated. to angiotensin I by renin and then converted to angiotensin II by ACE. ACE also is the major enzyme that degrades BK to BK FXII There are conflicts between human clinical and 1–5 (RPPGF) in the intravascular compartment (Fig. 2). experimental animal data for the role of FXII in thrombosis Angiotensin II usually binds to angiotensin receptor 1 to induce risk. A polymorphism in FXII (46C/T) is associated with vasoconstriction and salt retention, and elevate blood pressure. increased risk for arterial thrombosis [63–65]. Individuals However, if angiotensin receptor 2 is overexpressed, angiotensin homozygous for the 46C/T polymorphism have lowered FXII II will preferentially bind to it to induce vasodilatation and and FXIIa levels. Reduced activated forms of FXII may be blood pressure reduction. The mechanism by which the B2R associated with reduced total fibrinolytic activity, resulting in knockout mice are protected from thrombosis is 3-fold. Firstly, increased thrombosis risk. This interpretation is opposite to in the absence of B2R, angiotensin receptor 2 is overexpressed what is demonstrated in FXII-deficient mice [7]. FXII-deficient (Fig. 2). B2R and angiotensin receptor 2 colocalize in cells, and mice have reduced thrombus after induction of arterial clots there is an as yet unrecognized mechanism whereby the presence [7,66]. The mechanism for the increased size of thrombus in of one GPCR receptor regulates the expression of the other mice that have normal levels of FXII may be related to [8,62]. Secondly, there is increased angiotensin II as a result of increased contact activation occurring on a developing platelet reduced BK uptake into cells with reflexive increased ACE thrombus [14,15]. Therapeutic inhibition of FXII may result in degradative activity [8] (Fig. 2). The increased angiotensin II reduced thrombus formation without bleeding. These observations were not predicted by in vitro investigations on the biochemistry and cell biology of FXII and clinical studies on populations with polymorphisms or defects in FXII. Cellular activities of the plasma KKS Cell proliferation and angiogenesis Investigations have shown that kininogen and related proteins influence cellular activities of endothelial and other cells. These investigations were prompted by the observation that HKa induces selective apoptosis of proliferating endothelial cells and inhibits angiogenesis [67,68]. HKa inhibits neovascularization of s.c. planted Matrigel plugs, as well as fibroblast growth factor 2-induced angiogenesis in the chick chorioallantoic membrane Fig. 2. Mechanisms for thrombosis protection in bradykinin B2 receptor assay [67,68]. Moreover, peptides from domain 5 of HK (D5), (B2R) knockout mice. In the absence of B2R, there is increased plasma which subsumes the HK cell-binding region, induce endothelial bradykinin, as B2R accounts for 40% of the metabolism of bradykinin. cell apoptosis, inhibit angiogenesis, and are antibacterial Increased bradykinin results in increased conversion to bradykinin 1–5 (peptide RPPGF) (Blood 2006; 108: 192–99). As a byproduct of increased [69–71]. Kininogen-deficient Brown Norway Katholiek rats, RPPGF formation, there are increased levels of angiotensin II (Blood alternatively, display decreased angiogenesis, possibly resulting 2006; 108: 192–99). Angiotensin-converting enzyme (ACE) also converts from deficient BK release that is ameliorated by a BK analog or angiotensin I to angiotensin II. In the absence of B2R, there is increased kininogen replacement [72,73]. The mechanism(s) by which expression of the angiotensin receptor 2 (AT2R). The increased angio- these activities occur is not known, but may involve the anti- tensin II is shunted to overexpressed AT2R, as angiotensin II has the same binding affinity for angiotensin receptor 1 and AT2R. This leads to a adhesive function of HKa towards cells on vitronectin, the paradoxical effect in comparison to the usual angiotensin II elevation. kininogen multiprotein receptor complex, or tropomyosin Increased stimulation of AT2R produces vasodilatation and increased [30,74,75]. plasma nitric oxide (NO) and prostacyclin (PGI2) (Blood 2006; 108: 192– 99). The increased NO and PGI2 prolong the bleeding time, and these Outside-in signaling mediated by the KKS Although the animals have delayed thrombosis risk on the Rose Bengal model for carotid artery thrombosis. These investigations indicate that thrombosis proangiogenic activities of the KKS are mediated by B1R and risk can be modified by factors independent of coagulation, fibrinolytic or B2R, a different receptor system(s) may be involved in the anticoagulant proteins. inhibition of cell proliferation, adhesion, anti-apoptosis and Ó 2007 International Society on Thrombosis and Haemostasis
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