Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mature neutrophils in the circulation contain, besides the different proteases known for a long time, a recently discovered proteolytically inactive elastase homologue (HBP/CAP37/azurocidin). This homologue, which we have named HBP due to its strong affinity to heparin, is a chemoattractant for monocytes and has been shown to induce reversible detachment and contraction when added to monolayers of endothelial cells or fibroblasts. HBP may therefore play a pivotal role in leukocyte migration in response to inflammation. In this report a comparison of CH3O-Suc-Ala-Ala-Pro-Val-CH2Cl-inhibited elastase with HBP, its naturally occurring homologue selectively mutated in active serine and histidine, reveals that homotypic aggregation of monocytes and contraction of fibroblasts is specific for HBP. HBP induces thrombospondin secretion from monocytes four times as efficiently as the inhibited elastase, and the same molecule was found unable to compete for a specific saturable binding of HBP to monocytes with an apparent KD of 3 x 10(-8)M.
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PMID:Comparison of the effects of methoxysuccinyl-Ala-Ala-Pro-Val-chloromethyl ketone-inhibited neutrophil elastase with the effects of its naturally occurring mutationally inactivated homologue (HBP) on fibroblasts and monocytes in vitro. 149 75

Heparin-binding protein (HBP; also known as CAP37 or azurocidin) is a member of the serine proteinase family. Evolution, however, has reverted this protein into a non-proteolytic form by mutation of two of the three residues of the active-site triad. Although proteolytically inactive, the human heparin-binding protein (hHBP) is still capable of binding bovine pancreatic trypsin inhibitor (BPTI). This was demonstrated by affinity chromatography to BPTI immobilized on a solid matrix and by studies on plasmin inhibition kinetics. hHBP competes with plasmin for BPTI and this effect on plasmin inhibition has been analyzed in terms of a kinetic model. A dissociation constant, Kd = 0.1 microM, was found for the interaction between BPTI and hHBP. The hHBP provides an example of a serine proteinase which has lost its catalytic function by reverting residues of the active center while still preserving its capability of specific interactions with Kunitz inhibitors. pHBP, the porcine counterpart to hHBP, on the other hand, was incapable of BPTI binding. The structural basis for the BPTI binding to the human protein and the species difference is discussed in terms of putative three-dimensional structures of the proteins derived by comparative molecular modelling methods.
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PMID:Binding of bovine pancreatic trypsin inhibitor to heparin binding protein/CAP37/azurocidin. Interaction between a Kunitz-type inhibitor and a proteolytically inactive serine proteinase homologue. 768 80

Activated polymorphonuclear leukocytes release heparin-binding protein (HBP; also known as CAP37 or azurocidin) from azurophilic granules. HBP is a strong chemoattractant for monocytes that also prolongs monocyte survival and potentiates endotoxin (lipopolysaccharide [LPS])-induced production of tumor necrosis factor alpha (TNF-alpha). We investigated the binding of fluorescein isothiocyanate-conjugated HBP to human monocytes in the presence of EDTA and the polysaccharide fucoidan. EDTA, which chelates divalent cations, has been widely used to study the role of divalent cations in receptor-ligand interactions or enzyme activity. Fucoidan has been used to inhibit the binding of various ligands to scavenger receptors or selectins. Scavenger receptors are multiligand receptors that mediate endocytosis of proteases, protease-inhibitor complexes, lipoproteins, and LPS-lipid A. Fucoidan also interferes with leukocyte rolling by binding to L-selectins (expressed on leukocytes) and P-selectins (expressed on platelets and endothelium). We demonstrate that the binding of the neutrophil-derived protein HBP to monocytes is inhibited in the presence of EDTA and fucoidan. In addition, fucoidan and EDTA abrogate the enhancing effect of HBP on LPS-induced TNF-alpha production. These data provide supporting evidence that HBP binds to a receptor expressed on monocytes. This receptor is dependent on divalent cations and is possibly related to the scavenger receptor. Furthermore, we demonstrate that fucoidan, by itself, stimulates TNF-alpha release from isolated monocytes in a CD14-independent fashion. This is an important finding for the interpretation of results from studies that use fucoidan to "block" either scavenger receptors or L- or P-selectins.
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PMID:Modulation of lipopolysaccharide-induced monocyte activation by heparin-binding protein and fucoidan. 982 63

Azurocidin/CAP37/HBP is an antimicrobial and chemotactic protein that is part of the innate defenses of human neutrophils. In addition, azurocidin is an inactive serine protease homolog with binding sites for diverse ligands including heparin and the bovine pancreatic trypsin inhibitor (BPTI). The structure of the protein reveals a highly cationic domain concentrated on one side of the molecule and responsible for its strong polarity. To investigate the role of this highly basic region, we produced three recombinant azurocidin mutant proteins that were altered in either one or both of two clusters of 4 basic residues located symmetrically on each side of a central cleft in the cationic domain. Two of the mutant proteins (Loop 3: R5Q, K6Q, R8Q, and R10Q; Loop 4: R61Q, R62Q, R63Q, and R65Q) exhibited little or no change in heparin and BPTI binding or in antimicrobial function. In contrast, the Loop 3/Loop 4 mutant (R5Q, K6Q, R8Q, R10Q, R61Q, R62Q, R63Q, and R65Q) in which all 8 basic residues were replaced showed greatly decreased ability to bind heparin and to kill Escherichia coli and Candida albicans. Thus, we report that the 8 basic residues that were altered in the Loop 3/Loop 4 mutant contribute to the ability of the wild-type azurocidin molecule to bind heparin and to kill E. coli and C. albicans. Because BPTI binding was comparable in wild-type and Loop 3/Loop 4 mutant protein, we conclude that the same 8 basic residues are not involved in the binding of BPTI to azurocidin, supporting the notion that the binding site for BPTI is distinct from the site involved in heparin binding and antimicrobial activity. Finally, we show that removal of all 4 positively charged amino acids in the 20-44 azurocidin sequence (DMC1: R23Q,H24S,H32S,R34Q), a region previously thought to contain an antimicrobial domain, does not affect the activity of the protein against E. coli, Streptococcus faecalis, and C. albicans.
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PMID:Basic residues in azurocidin/HBP contribute to both heparin binding and antimicrobial activity. 1199 86

Heparin-binding protein (HBP; CAP37/azurocidin) is secreted from neutrophil leukocytes early during inflammation and plays a central role in early capillary leakage and extravasation of neutrophils. Furthermore, HBP is chemotactic towards monocytes and lymphocytes and protects against stress-induced apoptosis, e.g. induced by oxygen radicals released during inflammation. Thus, administration of HBP as an adjunct to antibiotics increased survival of mice with peritonitis. In the present study, the effects of recombinant HBP as an adjunct to standard antibiotics were examined in a porcine model of Actinobacillus pleuropneumoniae-induced pneumonia. Beneficial and possible adverse effects of HBP were evaluated clinically and pathologically as well as by measurement of clinical chemical variables and markers of inflammation (interleukin-6 and C-reactive protein) and oxidative stress (ascorbic acid and alpha-tocopherol). Pigs receiving HBP (0.55 mgkg-1, n=11) as a 6-hourly subcutaneous infusion starting 1-h post-infection had a faster decrease in rectal temperature compared to control animals receiving a carrier-infusion (n=11), with a significant lower temperature at 32 h post-infection (p<0.05). This difference was, however, transient and the temperature curves had a similar course from 38 h and onwards. The transient effect of HBP might be explained by the dosage regimen that was used. No signs of adverse effects of the HBP-infusion were observed. More studies are needed to elucidate of the effects of HBP further and to optimise the dosage regimen for further improvement the efficacy and safety.
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PMID:Effects of heparin-binding protein (CAP37/azurocidin) in a porcine model of Actinobacillus pleuropneumoniae-induced pneumonia. 1582 30

The leukocyte response in inflammation is characterized by an initial recruitment of polymorphonuclear leukocytes (PMN) preceding a second wave of monocytes to the site of injury or infection. In the mouse, 2 populations of monocytes have been identified, Gr1(-)CCR2(-)CX3CR1(hi) resident monocytes and Gr1(+)CCR2(+)CX3CR1(lo) inflammatory monocytes. Here, intravital microscopy of the musculus cremaster and a subcutaneous air pouch model were used to investigate a possible link between PMN extravasation and the subsequent emigration of inflammatory monocytes in response to local stimulation with PAF. In mice that were made neutropenic by injection of a PMN-depleting antibody, the extravasation of inflammatory monocytes, but not resident monocytes, was markedly reduced compared with mice with intact white blood cell count but was restored by local treatment with secretion of activated PMN. Components of the PMN secretion were found to directly activate inflammatory monocytes and further examination revealed PMN-derived LL-37 and heparin-binding protein (HBP/CAP37/azurocidin) as primary mediators of the recruitment of inflammatory monocytes via activation of formyl-peptide receptors. These data show that LL-37 and HBP specifically stimulate mobilization of inflammatory monocytes. This cellular cross-talk functionally results in enhanced cytokine levels and increased bacterial clearance, thus boosting the early immune response.
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PMID:Neutrophil secretion products pave the way for inflammatory monocytes. 1849 May 16