Kinetics of inhibition of platelet calpain II by human kininogens

Bradford, Harlan N.; Colman, Robert W.

doi:10.1042/bj2700083

Cited by 26 publications

(16 citation statements)

References 36 publications

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“…4 Calpain, a calcium-activated intracellular cysteine protease, is inhibited by HK and LK, with a K i equal to 2 and 0.5 nmol/L, respectively. 21 Although calpain is present in the cytosol in resting platelets, when they are activated, calpain translocates to the external membrane, 22,23 where it can be inhibited by kininogen. Although calpain inhibition can modulate platelet aggregation, 24 it cannot prevent the earliest phases of platelet activation, because that effect requires the prior translocation.…”

Section: Discussionmentioning

confidence: 99%

Kininogens Are Antithrombotic Proteins In Vivo

Colman

White

Scovell

et al. 1999

ATVB

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Abstract-Kininogens have recently been shown to possess antiadhesive, anticoagulant, and profibrinolytic properties and can inhibit platelet activation at low thrombin concentrations. To test whether kininogens have antithrombotic properties in vivo, we devised a model of limited arterial injury confined to removal of the endothelium. Brown-Norway Katholiek strain rats with an absence of low-and high-molecular-weight kininogen due to a single point mutation, A163T, were compared in the thrombosis model to the wild-type animals, which were otherwise genetically identical. Despite an equivalent vascular injury, the mean time (ϮSEM) for a 90% decrease in flow measured by laser Doppler was 38.4Ϯ17 minutes in the kininogen-deficient rats compared with 194Ϯ29 minutes in the wild-type animals (PϽ0.002). Key Words: arterial thrombosis Ⅲ kininogens Ⅲ antithrombotic Ⅲ fibrinolysis Ⅲ rats K ininogens are plasma proteins first recognized as the precursors of a peptide, bradykinin, which was liberated by plasma kallikrein. 1 Bradykinin can reproduce many inflammatory changes, including edema, pain, vasodilation, and increased vascular permeability. A deficiency of plasma high-(HK) and low-(LK) molecular-weight kininogens 2 in humans does not lead to a hemorrhagic disorder, despite a marked prolongation of the activated partial thromboplastin time. In fact, cloning 3 and delineation of the structurefunction relationships of kininogen have revealed new properties of this protein, including cysteine protease inhibition, 4 modulation of thrombin-induced platelet aggregation, 5 antiadhesive properties, 6 and profibrinolytic potential. 7 HK and LK have been divided into domains D1, D2, and D3, which compose the common heavy-chain N-terminal to domain D4, which contains the bradykinin sequence. LK contains a small domain, D5 L , whereas HK contains the large domains D5 H and D6, which compose the light chains. 3 The ability of D2 of the kininogens to inhibit platelet calpain 4 has been linked to an inhibition of thrombin-induced platelet aggregation, 8 whereas inhibition of the binding of thrombin to platelets by D3 of kininogens has led to a 10-fold shift in the doseresponse curve of thrombin-induced platelet activation. 9 HK can compete for fibrinogen binding to neutrophils 10 by competing for a site on the integrin Mac-1 11 and thus, limit the adhesion of neutrophils to artificial and biological surfaces. Peptides from D6 of HK can downregulate urokinasedependent plasminogen activation on human endothelial cells 7 by inhibiting the binding of prekallikrein to HK.All of these studies suggest that HK should serve as an antithrombotic protein. Conversely, individuals deficient in HK should manifest a prothrombotic state. Unfortunately, HK deficiency is a rare condition, and only a very small number of individuals have been observed in a serial fashion. Therefore, to test this hypothesis, we decided to use a well-defined animal model. Fortunately, a natural "knockout" exists in the Katholiek strain of the Brown-Norway rat. These rat...

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Section: Discussionmentioning

confidence: 99%

Kininogens Are Antithrombotic Proteins In Vivo

Colman

White

Scovell

et al. 1999

ATVB

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“…The cells were fed every 7 days and diluted to the initial seeding density. Cells growing at a density of 4 x 106/ml secrete approximately 25 (28) and was assayed by measuring the hydrolysis of a specific peptide substrate, 3-carboxypropionyl-leutyr-NH-7-(4-methyl) coumarylamide, which liberates a fluorescent product (29). The dialyzed enzyme and buffer (or inhibitor) were mixed and immediately added to a rectangular quartz cuvette at 25°C containing 1 mM peptide substrate in 60 mM Tris/HCl buffer, pH 7.5, 2.5% (v/v) dimethylsulfoxide (DMSO) and 5 mM CaCl2.…”

Section: Methodsmentioning

confidence: 99%

p-Benzoquinone, a reactive metabolite of benzene, prevents the processing of pre-interleukins-1 alpha and -1 beta to active cytokines by inhibition of the processing enzymes, calpain, and interleukin-1 beta converting enzyme.

Kalf

Renz

Niculescu

1996

Environ Health Perspect

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Chronic exposure of humans of benzene affects hematopoietic stem and progenitor cells and leads to aplastic anemia. The stromal macrophage, a target of benzene toxicity, secretes interleukin-1 (IL-1), which induces the stromal fibroblast to synthesize hematopoietic colony-stimulating factors. In a mouse model, benzene causes an acute marrow hypocellularity that can be prevented by the concomitant administration of IL-1 alpha. The ability of benzene to interfere with the production and secretion of IL-1 alpha was tested. Stromal macrophages from benzene-treated mice were capable of the transcription to the IL-1 alpha gene and the translation of the message but showed an inability to process the 34-kDa pre-IL-1 alpha precursor to the 17-kDa biologically active cytokine. Treatment of normal murine stromal macrophages in culture with hydroquinone (HQ) also showed an inhibition in processing of pre-IL-1 alpha. Hydroquinone is oxidized by a peroxidase-mediated reaction in the stromal macrophage to p-benzoquinone, which interacts with the sulfhydryl (SH) groups of proteins and was shown to completely inhibit the activity of calpain, the SH-dependent protease that cleaves pre-IL-1 alpha. In a similar manner, HQ, via peroxidase oxidation to p-benzoquinone, was capable of preventing the IL-1 beta autocrine stimulation of growth of human B1 myeloid tumor cells by preventing the processing of pre-IL-1 beta to mature cytokine. Benzoquinone was also shown to completely inhibit the ability of the SH-dependent IL-1 beta converting enzyme. Thus benzene-induced bone marrow hypocellularity may result from apoptosis of hematopoietic progenitor cells brought about by lack of essential cytokines and deficient IL-1 alpha production subsequent to the inhibition of calpain by p-benzoquinone and the prevention of pre-IL-1 processing. Images Figure 2. Figure 3. Figure 6. Figure 7. Figure 8.

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“…The cause of the unregulated calpain activity found in TTP is unclear, but earlier studies have shown that calpain association with microparticles in the plasma offers protection from inhibition (Kelton et al, 1992). In normal plasma, HK is both an important inhibitor of calpain as well as a potential substrate for calpain (Muller-Esterl et al, 1985;Schmaier et al, 1986a, b;Higashiyama et al, 1986;Salvesen et al, 1986;Bradford et al, 1990). The effect of the unregulated calpain activity in TTP on the patients' plasma HK has yet to be determined.…”

Section: Coagulation Studiesmentioning

confidence: 99%

“…HK inhibits calpain through a region on domain 2 (D2) of the heavy chain. Calpain can also proteolyse HK, resulting in characteristic subunits of 100 kD, 75 kD, and minor fragments (Schmaier et al, 1986a, b;Bradford et al, 1990;Van Iwaarden & Bourma, 1987). As well as functioning as a protease inhibitor of calpain and the lysosomal thiol cathepsin proteases (Salvesen et al, 1986), HK contributes, in vitro, to coagulation initiated by contact activation.…”

mentioning

confidence: 99%

“…Along with low molecular weight kininogen and a 2 -macroglobulin, one of the principal plasma inhibitors of calpain is high molecular weight kininogen (HK) (MullerEsterl et al, 1985;Schmaier et al, 1986a, b;Higashiyama et al, 1986;Salvesen et al, 1986;Bradford et al, 1990), a singlechain glycoprotein with a molecular weight of 120 kD (DeLa Cadena & Colman, 1991;Kerbiriou & Griffin, 1979). HK was originally thought to be the source of kinin in inflammatory disorders.…”

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confidence: 99%

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Proteolytic Degradation of High Molecular Weight Kininogen in Acute Thrombotic Thrombocytopenic Purpura

et al. 1997

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Summary. Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by thrombocytopenia and schistocytic haemolytic anaemia. The majority of patients have normal coagulation parameters including the activated partial thromboplastin time (APTT). An intracellular cysteine protease, calpain, has been found in the plasma of many patients with acute TTP, and we hypothesize that it participates in the pathogenesis of the disorder. However, certain aspects of the disorder remain unresolved. For example, high molecular weight kininogen (HK) is one of the primary plasma inhibitors of calpain, and it also can act as a substrate for calpain. Consequently, one might anticipate that the HK could be defective or altered in TTP. In this report we describe the analysis of HK in plasma from five patients with acute TTP and following recovery. The HK was studied immunogenically and functionally. We observed that the HK in plasma samples from patients with acute TTP was proteolysed. This degradation was not observed in remission samples from the same patients. However, both acute and remission TTP samples had normal HK coagulant activity (acute samples,x ¼ 0 . 84 Ϯ 0 . 26 U/ml; remission samples,x ¼ 0 . 89 Ϯ 0 . 21 U/ml; control samples, x ¼ 0 . 87 Ϯ 0 . 05 U/ml). Although the TTP plasmas were able to inhibit calpain activity, less inhibition activity was found in the acute samples (acute: mean inhibition 71 Ϯ 2 . 4%; remission: mean 92 Ϯ 2 . 1%; control samples: mean 93 Ϯ 5 . 4%: P < 0 . 001). Normal HK treated with calpain also had reduced calpain inhibition capacity (mean 58%). This study suggests that although HK is proteolysed during acute TTP, the proteolysis occurs without a major loss in the coagulation function or depletion of the protease inhibitory activity of HK.

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Kinetics of inhibition of platelet calpain II by human kininogens

Cited by 26 publications

References 36 publications

Kininogens Are Antithrombotic Proteins In Vivo

Kininogens Are Antithrombotic Proteins In Vivo

p-Benzoquinone, a reactive metabolite of benzene, prevents the processing of pre-interleukins-1 alpha and -1 beta to active cytokines by inhibition of the processing enzymes, calpain, and interleukin-1 beta converting enzyme.

Proteolytic Degradation of High Molecular Weight Kininogen in Acute Thrombotic Thrombocytopenic Purpura

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