Studies on the Interaction between Collagen and a Plasma Kallikrein-Like Activity EVIDENCE FOR A SURFACE-ACTIVE ENZYME SYSTEM

Harpel, Peter C.

doi:10.1172/jci106983

Cited by 32 publications

(16 citation statements)

References 36 publications

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“…This is consistent with the recent demonstration of the binding of plasma kallikrein to collagen and the kinin-releasing capability of the surface-bound kallikrein (20).…”

Section: Resultssupporting

confidence: 92%

A Study of the Plasma Kinin-generating System in Children with the Minimal Lesion, Idiopathic Nephrotic Syndrome

Kallen

Lee

1975

Pediatr Res

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705the present ones which suggest the existence of a photochemical reaction between D N A and bilirubin are somewhat disquieting, particularly when one considers that mutagens and chemical carcinogens derive their biologic activity from the ability to react with DNA. Our results suggest that phototherapy of neonates is a complex process which may generate a number of potentially dangerous genetic side effects. S U M M A R YThe widespread use of phototherapy in the treatment of neonatal jaundice is causing concern because little information is available on its effects on subcellular structure and function. The present study deals with the effects on the macromolecular structure of D N A illuminated in the presence of bilirubin. The results indicate a bilirubin-induced photodegradation of this biopolymer. ExtractAlthough the precise etiologic incitant of the minimal lesion idiopathic nephrotic syndrome of childhood is not known, it is likely that a host mechanism mediates the permeability alterations of the glomerular capillary wall resulting in massive proteinuria. As a first step in examining the possibility that local kinin release may account for the proteinuria in this disorder, two parameters of the plasma kinin-generating system, plasma prekallikrein and kallikrein inhibitor, were assayed during 27 nephrotic episodes in 21 corticosteroid-responsive children. Plasma kallikrein was assayed by means of its esterase activity on a synthetic arginine ester substrate, N-a-tosyl-L-arginine methyl ester (TAMe), after activation of Hageman factor by kaolin. This activity, after subtraction of spontaneous arginine esterase activity (i.e., TAMe esterase activity measured in plasma not exposed to kaolin) is derived from prekallikrein. Plasma prekallikrein activity in 11 normal children was 99.6 + 2.9 pnol TAMe hydrolyzed/ml plasma/hr (mean + SEM). Kallikrein inhibitor was quantified in arbitrary units. Kallikrein inhibitor activity in 11 normal children was 0.94 + 0.04 units.During the overt nephrotic syndrome, before initiation of intensive daily corticosteroid treatment, mean values were: prekallikrein, 58.5 A 7.24 flmol/ml/hr; and kallikrein inhibitor, 0.35 + 0.06 units. After corticosteroid-induced remission occurred, mean values were: plasma prekallikrein, 118.6 + 3.2 pmol/ml/hr; and kallikrein inhibitor, 0.78 + 0.03 pmol/ml/hr. Both parameters were again assayed in 14 of the 21 children after complete cessation of corticosteroid treatment. Plasma prekallikrein was normal, 99.6 * 4.8 flmol/ml/hr; but kallikrein inhibitor was still somewhat depressed, 0.84 + 0.03 units. A subset of 9 patients had marked depression of plasma prekallikrein to levels less than 20 pmol/ml/hr and essentially undetectable inhibitor acGvity. Serum a-2 macroglobulin was elevated in nephrotic patients: mean value during relapse, 862 + 29 mg/100 ml; during corticosteroid-maintaining remission, 615 * 29 mg/100 ml. After cessation of corticosteroids, mean serum level was 481 + 20 mg/100 ml. The proportional reduction of plasma prekallikrein an...

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“…This is consistent with the recent demonstration of the binding of plasma kallikrein to collagen and the kinin-releasing capability of the surface-bound kallikrein (20).…”

Section: Resultssupporting

confidence: 92%

A Study of the Plasma Kinin-generating System in Children with the Minimal Lesion, Idiopathic Nephrotic Syndrome

Kallen

Lee

1975

Pediatr Res

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“…To provide even stronger evidence that all detectable fibrinogenolytic activity was closely associated with a2-macroglobulin, the relationship of a2-macroglobulin to its proteolytic activity was further explored by immunoprecipitation. An IgG fraction, itself possessing no antiplasmin activity as demonstrated by a fibrinolytic assay (39), having antibody specific for a2-macroglobulin, was added in optimal amounts (40) to the a2-macroglobulin prepared from urokinasetreated plasma. After removal of the precipitate which formed after an 18-h incubation at 40C, the supernatant fluid contained no detectable a2-macroglobulin as determined by electroimmunoanalysis (28).…”

Section: Resultsmentioning

confidence: 99%

Degradation of Human Fibrinogen by Plasma α2-Macroglobulin-Enzyme Complexes

Harpel¹,

Mosesson²

1973

J. Clin. Invest.

Self Cite

159

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A B S T R A C T This study demonstrates that human plasma a2-macroglobulin preparations possess an enzymic activity that degrades fibrinogen, resulting in the formation of products whose structure resembles that of circulating fibrinogen catabolites. The sequence of degradation is similar to that observed in plasmincatalyzed digests, in that Aa-chain fragmentation precedes that of B,8-chain. The addition of plasminogen activators to plasma induced an increase in the N-atosyl-L-arginine methyl ester HCl esterase and fibrinogenolytic activity associated with a2-macroglobulin purified from this plasma, indicating that the enzymic activity of the complex was preserved and could be increased in the presence of other plasma enzyme inhibitors. Immunochemical studies demonstrated that an a2-macroglobulin-plasmin complex had formed in urokinase-treated plasma. This a2-macroglobulin preparation manifested an esterolytic profile like that of a complex prepared from plasmin and purified a2-macroglobulin. After complex formation with a2-macroglobulin in plasma, plasmin retained less than 0.1% of its fibrinogenolytic activity. That plasmin expressed its activity while bound to a2-macroglobulin was suggested by immunoprecipitation of this activity with aa-macroglobulin antibody and by the demonstration that pancreatic trypsin inhibitor did not effectively inhibit its fibrinogenolytic or esterolytic activity. These results raise the possibility that, in addition to its activity as a major plasma proteolytic enzyme inhibitor, a2-macroglobulin may modThis paper was presented in part at the 15th Annual Meeting,

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“…The values given are derived from integration of reduced radiolabeled prekallikrein in the 85,000 Mr uncleaved molecule and the 48,000 Mr cleavage fragment shown in Fig. 2 Harpel (34) showed that partially purified kallikrein would bind to collagen and that, after brief incubation of particulate collagen with undiluted plasma, kallikrein activity could -be identified on the washed collagen. Assuming …”

Section: Factor XImentioning

confidence: 99%

Role of high-molecular-weight kininogen in surface-binding and activation of coagulation Factor XI and prekallikrein.

Wiggins¹,

Bouma²,

Cochrane³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

178

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In the contact phase of activation of the kinin-forming, intrinsic clotting, and fibrinolytic systems, high-molecular-weight kininogen acts as a cofactor for the activation of Factor XI, prekallikrein, and Hageman factor. One mechanism by which high-molecular-weight kininogen acts as a cofactor has been studied by using 125f-labeled Factor XI and prekallikrein in kaolin-activated normal human plasma and plasmas deficient in high-molecular-weight kininogen and Hageman factor. High-molecular-weight kininogen was found to be essential for normal binding and cleavage of both Factor XI and prekallikrein on the kaolin surface. Hageman factor was essential for cleavage but not for binding of Factor XI and prekallikrein to kaolin. In normal plasma 80% of the activated Factor XI remained surface-bound, whereas 80% of the kallikrein was not surface-bound. These findings are consistent with the hypothesis that, in the initial phase of contact activation, high-molecular-weight kininogen links both Factor XI and prekallikrein to the exposed surface where they are activated by surface-bound activated Hageman factor. Once activated, the Factor XI molecules remain localized at the site of activation, in contrast to the kallikrein molecules which are found largely in the surrounding plasma.Activation of Hageman factor (Factor XII) upon a negatively charged surface initiates intrinsic coagulation, fibrinolysis, and the generation of vasoactive peptides (1-5). High-molecularweight (Mr) kininogen is a cofactor for the optimal activation of surface-bound Hageman factor by kallikrein (6-8) and for the activation of prekallikrein and Factor XI by surface-bound activated Hageman factor (6-8). Prekallikrein is complexed to high Mr kininogen in plasma (9). Recent studies (10; R. C. Wiggins, B. N. Bouma, C. G. Cochrane, and J. H. Griffin, unpublished data) suggest that Factor XI is also complexed to high Mr kininogen in plasma. In this study we demonstrate that one mechanism by which high Mr kininogen acts as a cofactor for the activation of both Factor XI and prekallikrein in plasma is to bind both these molecules to the surface where they are activated by surface-bound activated Hageman factor. We also demonstrate that, while activated Factor XI remains associated with the surface, kallikrein dissociates from the surface. MATERIALS AND METHODS Purified proteinsFactor XI was isolated from normal human plasma as described elsewhere (11) and was determined to be more than 95% homogeneous on sodium dodecyl sulfate (NaDodSO4/polyacrylamide gels. The purified protein had a specific clotting activity of 220 units/mg, where 1 clotting unit is defined as the amount of activity present in 1 ml of citrated normal human plasma. Factor XI was radiolabeled with '25iodine by the insolubilized lactoperoxidase method (12). The 125I-labeled Factor XI (125I-Factor XI), 5 ,uCi/,ug, retained its procoagulant activities at 3.6 clotting units/ml.Prekallikrein was isolated from normal human plasma by a method similar to that described for Factor XI (11...

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Studies on the Interaction between Collagen and a Plasma Kallikrein-Like Activity EVIDENCE FOR A SURFACE-ACTIVE ENZYME SYSTEM

Cited by 32 publications

References 36 publications

A Study of the Plasma Kinin-generating System in Children with the Minimal Lesion, Idiopathic Nephrotic Syndrome

A Study of the Plasma Kinin-generating System in Children with the Minimal Lesion, Idiopathic Nephrotic Syndrome

Degradation of Human Fibrinogen by Plasma α2-Macroglobulin-Enzyme Complexes

Role of high-molecular-weight kininogen in surface-binding and activation of coagulation Factor XI and prekallikrein.

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