scholarly journals Heparin accelerates the inhibition of cathepsin G by mucus proteinase inhibitor: potent effect of O-butyrylated heparin

1998 ◽  
Vol 330 (3) ◽  
pp. 1369-1374 ◽  
Author(s):  
Jacques ERMOLIEFF ◽  
Jérôme DURANTON ◽  
Maurice PETITOU ◽  
G. Joseph BIETH
Keyword(s):  
Proteinase Inhibitor ◽  
Anticoagulant Activity ◽  
Cathepsin G ◽  
Heparin Binding ◽  
Potent Effect ◽  
Heparin Binding Protein ◽  
Rate Acceleration ◽  
Eglin C ◽  
Heparin Derivative ◽  
Positively Charged

Heparin tightly binds cathepsin G and so protects the enzyme from inhibition by α1-antichymotrypsin, α1-proteinase inhibitor and eglin c, three proteins which do not bind heparin [Ermolieff J., Boudier C., Laine A., Meyer B. and Bieth J. G. (1994) J. Biol. Chem. 269, 29502-29508]. Here we show that heparin no longer protects cathepsin G from inhibition when the enzyme is reacted with mucus proteinase inhibitor (MPI), a heparin-binding protein. Heparin fragments of Mr = 4500 and 8100 and O-butyrylated heparin of Mr = 8000 form tight complexes with cathepsin G (Kd = 0.5-2.2 nM) and MPI (Kd = 0.4-0.8 μM) and accelerate the MPI-promoted inhibition of cathepsin G by a factor of 17-26. They also accelerate the inhibition of neutrophil elastase and pancreatic chymotrypsin. The rate acceleration is due to the binding of heparin to MPI. Butyrylation of heparin slightly decreases its affinity for cathepsin G and MPI but sharply decreases the ionic interactions between the positively charged proteins and the negatively charged polyanion. The butyrylated heparin derivative is the best rate accelerator: it increases the rate constant for the MPI-induced inhibition of cathepsin G and elastase by factors of 26 and 23, respectively. This, together with the fact that it has a good bioavailability and a very low anticoagulant activity, suggests that it might be an adjuvant of MPI-based therapy of cystic fibrosis.

Glycosaminoglycan: a candidate to stimulate the repair of chronic wounds

2005 ◽  
Vol 94 (07) ◽  
pp. 4-16 ◽  
Author(s):  
Philip V. Peplow
Keyword(s):  
Chronic Wounds ◽  
Binding Protein ◽  
Cathepsin G ◽  
Sustained Delivery ◽  
Heparin Binding ◽  
Anionic Polymers ◽  
Heparin Binding Protein ◽  
Persistent Inflammation ◽  
Large Numbers ◽  
Secretory Products

SummaryA persistent inflammation with large numbers of neutrophils is found in chronic wounds. Secretory products released from the neutrophils, which include proteinases and a heparin-binding protein, are detrimental to wound healing as they cause degradation of the extracellular matrix and growth factors, and promote further recruitment of neutrophils to the wound area. The neutrophil-derived elastase, cathepsin G, proteinase-3 and heparin-binding protein are cationic, and it is hypothesized that their effects can be inhibited by electrostatic binding with certain anionic polymers such as glycosaminoglycans or functionalized dextrans. A sustained delivery of such compounds alone or in combination from a biodegradable carrier may provide a stimulus for these wounds to pass to the next stage of repair.

Pharmacokinetics of Full Length and Two-Domain Tissue Factor Pathway Inhibitor in Combination with Heparin in Rabbits

1993 ◽  
Vol 70 (03) ◽  
pp. 454-457 ◽  
Author(s):  
Claus Bregengaard ◽  
Ole Nordfang ◽  
Per Østergaard ◽  
Jens G L Petersen ◽  
Giorgio Meyn ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Anticoagulant Activity ◽  
Fold Increase ◽  
Volume Of Distribution ◽  
Full Length ◽  
Heparin Binding ◽  
Extrinsic Pathway ◽  
C Terminus ◽  
Tissue Factor Pathway

SummaryTissue factor pathway inhibitor (TFPI) is a feed back inhibitor of the initial activation of the extrinsic pathway of coagulation. In humans, injection of heparin results in a 2-6 fold increase in plasma TFPI and recent studies suggest that TFPI may be important for the anticoagulant activity of heparin. Full length (FL) TFPI, but not recombinant two-domain (2D) TFPI, has a poly cationic C-terminus showing very strong heparin binding. Therefore, we have investigated if heparin affects the pharmacokinetics of TFPI with and without this C-terminus.FL-TFPI (608 U/kg) and 2D-TFPI (337 U/kg) were injected intravenously in rabbits with and without simultaneous intravenous injections of low molecular weight heparin (450 anti-XaU/kg).Heparin decreased the volume of distribution and the clearance of FL-TFPI by a factor 10-15, whereas the pharmacokinetics of 2D-TFPI were unaffected by heparin. When heparin was administered 2 h following TFPI the recovery of FL-TFPI was similar to that found in the group receiving the two compounds simultaneously, suggesting that the releasable pool of FL-TFPI is removed very slowly in the absence of circulating heparin.

Comparison of the Non-Specific Binding of Unfractionated Heparin and Low Molecular Weight Heparin (Enoxaparin) to Plasma Proteins

1993 ◽  
Vol 70 (04) ◽  
pp. 625-630 ◽  
Author(s):  
Edward Young ◽  
Benilde Cosmi ◽  
Jeffrey Weitz ◽  
Jack Hirsh
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Plasma Proteins ◽  
Low Molecular Weight Heparin ◽  
Specific Binding ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Heparin Binding ◽  
Fixed Amount

SummaryThe non-specific binding of anticoagulantly-active heparin to plasma proteins may influence its anticoagulant effect. We used low affinity heparin (LAH) essentially devoid of anti-factor Xa activity to investigate the extent and possible mechanism of this non-specific binding. The addition of excess LAH to platelet-poor plasma containing a fixed amount of unfractionated heparin doubled the anti-factor Xa activity presumably because it displaces anticoagulantly-active heparin from plasma proteins. Although dextran sulfates of varying molecular weights also increased the anti-factor Xa activity, less sulfated heparin-like polysaccharides had no effect. These findings suggest that the ability to displace active heparin from plasma protein binding sites is related to charge and may be independent of molecular size. In contrast to its effect in plasma containing unfractionated heparin, there was little augmentation in anti-factor Xa activity when LAH was added to plasma containing low molecular weight heparin (LMWH), indicating that LMWH binds less to plasma proteins than unfractionated heparin. This concept is supported by studies comparing the anticoagulant activity of unfractionated heparin and LMWH in plasma with that in buffer containing antithrombin III. The anti-factor Xa activity of unfractionated heparin was 2-fold less in plasma than in the purified system. In contrast, LMWH had identical anti-factor Xa activity in both plasma and buffer, respectively. These findings may be clinically relevant because the recovered anti-factor Xa activity of unfractionated heparin was 33% lower in plasma from patients with suspected venous thrombosis than in plasma from healthy volunteers. The reduced heparin recovery in patient plasma reflects increased heparin binding to plasma proteins because the addition of LAH augmented the anti-factor Xa activity. In contrast to unfractionated heparin, there was complete recovery of LMWH added to patient plasma and little increase of anti-factor Xa activity after the addition of LAH. These findings may explain why LMWH gives a more predictable dose response than unfractionated heparin.

scholarly journals Early prolonged neutrophil activation in critically ill patients with sepsis

2021 ◽  
Vol 27 (2) ◽  
pp. 192-200
Author(s):  
Sanna Törnblom ◽  
Sara Nisula ◽  
Suvi T Vaara ◽  
Meri Poukkanen ◽  
Sture Andersson ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Intensive Care Unit Admission ◽  
Plasma Concentrations ◽  
Neutrophil Activation ◽  
Early Event ◽  
Heparin Binding ◽  
Activation Markers ◽  
Heparin Binding Protein ◽  
Pro Inflammatory Cytokines

We hypothesised that plasma concentrations of biomarkers of neutrophil activation and pro-inflammatory cytokines differ according to the phase of rapidly evolving sepsis. In an observational study, we measured heparin-binding protein (HBP), myeloperoxidase (MPO), IL-6 and IL-8 in 167 sepsis patients on intensive care unit admission. We prospectively used the emergence of the first sepsis-associated organ dysfunction (OD) as a surrogate for the sepsis phase. Fifty-five patients (of 167, 33%) developed the first OD > 1 h before, 74 (44%) within ± 1 h, and 38 (23%) > 1 h after intensive care unit admission. HBP and MPO were elevated at a median of 12 h before the first OD, remained high up to 24 h, and were not associated with sepsis phase. IL-6 and IL-8 rose and declined rapidly close to OD emergence. Elevation of neutrophil activation markers HBP and MPO was an early event in the evolution of sepsis, lasting beyond the subsidence of the pro-inflammatory cytokine reaction. Thus, as sepsis biomarkers, HBP and MPO were not as prone as IL-6 and IL-8 to the effect of sample timing.

The heparin-binding protein interactome in pancreatic diseases

Pancreatology ◽  
2013 ◽  
Vol 13 (6) ◽  
pp. 598-604 ◽  
Author(s):  
Q.M. Nunes ◽  
V. Mournetas ◽  
B. Lane ◽  
R. Sutton ◽  
D.G. Fernig ◽  
...  
Keyword(s):  
Binding Protein ◽  
Heparin Binding ◽  
Pancreatic Diseases ◽  
Heparin Binding Protein ◽  
Protein Interactome

Heparin-binding protein (HBP/CAP37): A missing link in neutrophil-evoked alteration of vascular permeability

2001 ◽  
Vol 7 (10) ◽  
pp. 1123-1127 ◽  
Author(s):  
Narinder Gautam ◽  
A. Maria Olofsson ◽  
Heiko Herwald ◽  
Lars F. Iversen ◽  
Evy Lundgren-Åkerlund ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Binding Protein ◽  
Heparin Binding ◽  
Missing Link ◽  
Heparin Binding Protein

Human C21orf63 is a Heparin-binding Protein

2009 ◽  
Vol 146 (3) ◽  
pp. 369-373 ◽  
Author(s):  
Kanae Mitsunaga ◽  
Jun Harada-Itadani ◽  
Toshihide Shikanai ◽  
Hiroaki Tateno ◽  
Yuzuru Ikehara ◽  
...  
Keyword(s):  
Binding Protein ◽  
Heparin Binding ◽  
Heparin Binding Protein

Changing the inhibitory specificity and function of the proteinase inhibitor eglin c by site-directed mutagenesis: functional and structural investigation

Biochemistry ◽  
1992 ◽  
Vol 31 (37) ◽  
pp. 8755-8766 ◽  
Author(s):  
Dirk W. Heinz ◽  
Sven G. Hyberts ◽  
Jeff W. Peng ◽  
John P. Priestle ◽  
Gerhard Wagner ◽  
...  
Keyword(s):  
Proteinase Inhibitor ◽  
Structural Investigation ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Inhibitory Specificity ◽  
Eglin C ◽  
And Function

scholarly journals Heparin promotes fibrillation of most phenol soluble modulin peptides from S. aureus: a possible strengthening of the bacterial biofilm

2021 ◽  
Author(s):  
Zahra Najarzadeh ◽  
Masihuz Zaman ◽  
Vita Serekaité ◽  
Kristian Strømgaard ◽  
Maria Andreasen ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Bacterial Colonization ◽  
Bacterial Biofilm ◽  
Affinity Binding ◽  
Heparin Binding ◽  
Peptide Microarrays ◽  
Sulfated Glycosaminoglycan ◽  
Lysine Residues ◽  
Biophysical Techniques ◽  
Positively Charged

ABSTRACTPhenol soluble modulins (PSMs) are virulence peptides secreted by different Staphylococcus aureus strains. In addition, PSMs are able to form amyloid fibrils which may strengthen the biofilm matrix. The highly sulfated glycosaminoglycan heparin promotes S.aureus infection but the basis for this is unclear. We hypothesized that heparin promotes PSM fibrillation and in this way aids bacterial colonization. Here we address this hypothesis using a combination of different biophysical techniques along with peptide microarrays. We find that heparin accelerates fibrillation of all α-PSMs (except PSMα2) and δ-toxin, but inhibits β-PSMs’ fibrillation by blocking nucleation. Given that S. aureus secretes higher levels of α-PSMs than β-PSMs peptidess, heparin is likely to overall promote fibrillation. Heparin binding is driven by multiple positively charged lysine residues in α-PSMs and δ-toxins, whose removal strongly reduces affinity. Binding of heparin does not alter the final fibril conformation. Rather, heparin provides a scaffold to catalyze or inhibit fibrillation. Our findings suggest that heparin may strengthen bacterial biofilm through increased PSM fibrillation.Abstract Figure

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