The Heparin Binding Site and Activation of Protease Nexin I

Evans, Dyfed L.; Christey, Peter B.; Carrell, Robin W.

doi:10.1007/978-1-4684-8357-4_7

Cited by 24 publications

(29 citation statements)

References 8 publications

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“…[23][24][25] As such, it has been implicated in many cell processes, including coagulation, cell movement, and fi brinolysis. Following reports of SERPINE2 association with quantitative phenotypes of lung function among patients and COPD 8,9 and its presence in lung tissue from individuals with asthma and COPD, 8 SERPINE2 also has become an attractive Dutch hypothesis candidate gene.…”

Section: Discussionmentioning

confidence: 99%

Association of SERPINE2 With Asthma

Himes

Klanderman

Ziniti

et al. 2011

Chest

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A sthma and COPD are complex human airway diseases that are infl uenced by various genetic and environmental susceptibility factors. In 1961, Orie and colleagues 1 proposed that these diseases were different expressions of one basic pulmonary disease whose expression in individuals was shaped differently depending on a combination of endogenous (ie, host) and exogenous (ie, environmental) factors. This view, which became known as the "Dutch hypothesis," suggests that overlapping clinical features of asthma and COPD are partly based on an allergic diathesis and airways hyperresponsiveness (AHR). 2 Although there is some opposition to the original Dutch hypothesis, little doubt exists that common mechanisms underlie asthma and COPD. 3 Identifying genetic variants that infl uence some of these common mechanisms would provide important insights into both diseases.Genetic linkage studies of COPD, 4 asthma, 5,6 and general population lung function 7 have demonstrated linkage peaks on chromosome 2q, suggesting that in this region are good Dutch hypothesis candidate genes. This is further supported by linkage results observed on chromosome 2q for asthma and COPD being strongest for the FEV 1 /FVC phenotype. A promising Background: The "Dutch hypothesis" suggests that asthma and COPD have common genetic determinants. The serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2 ( SERPINE2 ) gene previously has been associated with COPD. We sought to determine whether SERPINE2 is associated with asthma and asthma-related phenotypes. Methods: We measured the association of 39 SERPINE2 single-nucleotide polymorphisms (SNPs) with asthma-related phenotypes in 655 parent-child trios from the Childhood Asthma Management Program (CAMP), and we measured the association of 19 SERPINE2 SNPs with asthma in a case-control design of 359 CAMP probands and 846 population control subjects. We attempted to replicate primary asthma-related phenotype fi ndings in one independent population and primary asthma affection status fi ndings in two independent populations. We compared association results with CAMP proband expression quantitative trait loci.

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Section: Discussionmentioning

confidence: 99%

Association of SERPINE2 With Asthma

Himes

Klanderman

Ziniti

et al. 2011

Chest

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“…Initial formation of a ternary complex of PN-1 with both thrombin and heparin may therefore be the first stage of a two-phase interaction, with the heparinthrombin interaction lost when the covalent PN-1-thrombin complex forms. Heparin is not released on the formation of the PN-1-thrombin complex (Evans et al, 1991), indicating that the PN-1/thrombin complex is likely to remain bound to the cell surface by HS.…”

Section: Other Heparin-activated Serpinsmentioning

confidence: 99%

“…This serpin has long been known to inhibit thrombin approximately 100-fold faster than AT in vitro (Wallace et al, 1989), and heparin enhances this rate by about three orders of magnitude (Evans et al, 1991). However, PN-1 does not contribute to the anticoagulant activity of heparin in vivo because its concentration in plasma is very low.…”

Section: Other Heparin-activated Serpinsmentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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“…17 Thus these 2 serpins are probably the main tissue regulators of plasmin generation and thrombin activity, respectively, and so play complementary roles.…”

mentioning

confidence: 99%

Macrophages and Platelets Are the Major Source of Protease Nexin-1 in Human Atherosclerotic Plaque

Mansilla

Boulaftali

Vénisse

et al. 2008

ATVB

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Objective-Protease nexin-1 (PN-1), a serpin constitutively expressed by vascular smooth muscle cells and endothelial cells, inhibits thrombin, plasminogen activators, and plasmin and can thus be expected to play a role in vascular biology. The present study addressed the question of PN-1 expression in human atherothrombosis. Methods and Results-Immunohistochemistry and biochemical studies confirmed that PN-1 was expressed at a moderate level in the medial layer of normal human arteries and showed that PN-1 expression was increased in atherothrombotic lesions. In early noncomplicated plaques, PN-1 was associated with infiltrating mononuclear cells. A strong PN-1 signal was observed in advanced lesions, principally in intraplaque hemorrhage-related structures. Monocytes/macrophages and platelets were identified as the main sources of PN-1 within atherothrombotic material. Isolated human monocytes and platelets both expressed high levels of active PN-1, and monocyte PN-1 expression was upregulated, at both messenger and protein levels, in response to stimulation by lipopolysaccharides. In contrast, PN-1 expression was downregulated during their differentiation into macrophages which were shown to produce degraded forms of PN-1. Key Words: protease nexin-1 Ⅲ atherosclerosis Ⅲ inflammatory cells Ⅲ thrombin A disequilibrium between proteases and antiproteases increasingly appears to be critical in the pathogenicity of atherothrombosis, via the modulation of the size of the plaque, its stability, and its progression toward rupture. Serine protease inhibitors, termed serpins, may be important in regulating protease activity in arterial lesions. Although plasma antithrombin could theoretically diffuse into the inner vessel layer when endothelial permeability is increased, no thrombin-antithrombin complexes could be detected in the vessel wall. 1 There is substantial evidence that plasminogen activator inhibitor (PAI)-1, an essential serpin of the fibrinolytic system, may contribute to the development of coronary artery disease. 2 However it is difficult to draw global conclusions regarding the role (protective or deleterious) of PAI-1 in the development of atherosclerosis. Conclusions-PlateletsVascular endothelial cells 3,4 and smooth muscle cells 5 produce another serpin named protease nexin-1 (PN-1). PN-1 is a powerful inhibitor of thrombin and also inhibits urokinase-type plasminogen activator (uPA), tissue plasminogen activator (tPA), and plasmin. Its action is potentiated by glycosaminoglycans (GAGs) such as heparan sulfates. 6 In contrast to antithrombin and PAI-1, PN-1 is barely detectable in plasma but is produced by various cell types. It was first identified in the central nervous system as glia-derived nexin and has been shown to inhibit the effects of thrombin on neuronal, as well as glial cells. 7 Pericellular serpins play a pivotal role in the physiology of tissue serine proteases. Catabolism of PN-1/protease complexes occurs in fibroblasts by internalization and intracellular degradation. 8 Recently PN-1...

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The Heparin Binding Site and Activation of Protease Nexin I

Cited by 24 publications

References 8 publications

Association of SERPINE2 With Asthma

Association of SERPINE2 With Asthma

Pharmacology of Heparin and Related Drugs

Macrophages and Platelets Are the Major Source of Protease Nexin-1 in Human Atherosclerotic Plaque

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