The Significance of Colocalization of Plasminogen Activator Inhibitor-1 and Vitronectin in Hepatic Fibrosis

Inuzuka, Sadataka; Ueno, Takato; Torimura, Takuji; Tamaki, Seishu; Sugawara, Hiroshi; Sakata, Ryuichiro; Kusaba, Nobuhide; Sata, Michio; Tanikawa, Ken

doi:10.3109/00365529709011224

Cited by 16 publications

(12 citation statements)

References 29 publications

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“…As such, immunological approaches have identified vitronectin as the major PAI‐1‐binding protein in the ECM of cultured endothelial cells 60. The co‐localization of the two proteins in vivo is well documented 61–65. Appropriate control of PAI‐1 function is vital not only to hemostasis but also for regulation of many activities in tissues, including inflammation, neurological activity, angiogenesis, and tumor growth 66–68.…”

Section: Discussionmentioning

confidence: 99%

Metals affect the structure and activity of human plasminogen activator inhibitor‐1. I. Modulation of stability and protease inhibition

et al. 2011

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Human plasminogen activator inhibitor type 1 (PAI-1) is a serine protease inhibitor with a metastable active conformation. Under physiological conditions, half of the inhibitor transitions to a latent state within 1-2 h. The interaction between PAI-1 and the plasma protein vitronectin prolongs this active lifespan by~50%. Previously, our group demonstrated that PAI-1 binds to resins using immobilized metal affinity chromatography (Day, U.S. Pat. 7,015,021 B2, March 21, 2006). In this study, the effect of these metals on function and stability was investigated by measuring the rate of the transition from the active to latent conformation. All metals tested showed effects on stability, with the majority falling into one of two types depending on their effects. The first type of metal, which includes magnesium, calcium and manganese, invoked a slight stabilization of the active conformation of PAI-1. A second category of metals, including cobalt, nickel and copper, showed the opposite effects and a unique vitronectin-dependent modulation of PAI-1 stability. This second group of metals significantly destabilized PAI-1, although the addition of vitronectin in conjunction with these metals resulted in a marked stabilization and slower conversion to the latent conformation. In the presence of copper and vitronectin, the halflife of active PAI-1 was extended to 3 h, compared to a half-life of only~30 min with copper alone. Nickel had the largest effect, reducing the half-life to~5 min. Together, these data demonstrate a heretofore-unknown role for metals in modulating PAI-1 stability.

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Section: Discussionmentioning

confidence: 99%

Metals affect the structure and activity of human plasminogen activator inhibitor‐1. I. Modulation of stability and protease inhibition

et al. 2011

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“…Plasminogen activator inhibitor (PAI)-1 is a major inhibitor of tissue-type plasminogen activator and u-PA and can therefore indirectly contribute to matrix deposition by preventing matrix dissolution. PAI-1 is consistently and dramatically up-regulated in a variety of fibrotic diseases (7)(8)(9). Furthermore, PAI-1-deficient mice are protected against ECM deposition and fibrosis in the lung after bleomycin challenge (10,11), whereas PAI-1 overexpressing mice suffer from extensive fibrotic changes (10).…”

Section: Clinical Relevancementioning

confidence: 99%

Cross-Talk between Human Mast Cells and Bronchial Epithelial Cells in Plasminogen Activator Inhibitor-1 Production via Transforming Growth Factor-β1

Lee

Kato

Takabayashi

et al. 2015

Am J Respir Cell Mol Biol

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Previous reports suggest that plasminogen activator inhibitor-1 (PAI-1) promotes airway remodeling and that human and mouse mast cells (MCs) are an important source of PAI-1. In the present study we investigated MC-epithelial cell (EC) interactions in the production of PAI-1. We stimulated the human MC line LAD2 with IgE-receptor cross-linking and collected the supernatants. We incubated the human bronchial EC line BEAS-2B with the LAD2 supernatants and measured the level of PAI-1. When the supernatants from IgE-stimulated LAD2 were added to BEAS-2B, there was a significant enhancement of PAI-1 production by BEAS-2B. When we treated the MC supernatants with a transforming growth factor (TGF)-b1 neutralizing antibody, the MC-derived induction of PAI-1 from BEAS-2B was completely abrogated. Although TGF-b1 mRNA was constitutively expressed in resting LAD2, it was not highly induced by IgE-mediated stimulation. Nonetheless, active TGF-b1 protein was significantly increased in LAD2 after IgE-mediated stimulation. Active TGF-b1 produced by primary cultured human MCs was significantly reduced in the presence of a chymase inhibitor, suggesting a role of MC chymase as an activator of latent TGF-b1. This study indicates that stimulation of human MCs by IgE receptor cross-linking triggers activation of TGF-b1, at least in part via chymase, which in turn induces the production of PAI-1 by bronchial ECs. Our data suggest that human MCs may play an important role in airway remodeling in asthma as a direct source of PAI-1 and by activating bronchial ECs to produce further PAI-1 via a TGF-b1-mediated activation pathway.

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“…Immunohistochemical evidence indicates that vitronectin and PAI-1 are intimately linked, and in fact have been shown to be co-localized to areas of special consideration, including those of sclerosis and necrosis of diseased tissues (28,29). Is the self-association of vitronectin triggered by PAI-1 a regulatory step in the turnover of tissue forms of vitronectin during times of tissue injury, necrosis, and wound remodeling?…”

Section: Fig 8 Pai-1-induced Multimerization Enhances the Binding Omentioning

confidence: 99%

Plasminogen Activator Inhibitor Type 1 Promotes the Self-association of Vitronectin into Complexes Exhibiting Altered Incorporation into the Extracellular Matrix

Minor¹,

Peterson

2002

Journal of Biological Chemistry

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Serine proteinase inhibitors, including plasminogen activator inhibitor type 1 (PAI-1) and antithrombin, are key regulators of hemostatic processes such as thrombosis and wound healing. Much evidence suggests that PAI-1 can influence such processes, as well as pathological events like tumor metastasis, through its ability to directly regulate binding of blood platelets and cells to extracellular substrata. One way that PAI-1 influences these processes may be mediated through its binding to the plasma protein vitronectin. Binding to PAI-1 results in the incorporation of vitronectin into a higher order complex with a potential for multivalent interactions (Podor, T. J., Shaughnessy, S. G., Blackburn, M. N., and Peterson, C. B. (2000) J. Biol. Chem. 275, 25402-25410). In this study, evidence is provided to support this concept from studies on the effects of PAI-1-induced multimerization on the interactions of vitronectin with matrix components and cell surface receptors. By monitoring complex formation and stability over time using sizeexclusion high performance liquid chromatography, a correlation is made between PAI-1-induced multimerization and enhanced cell/matrix binding properties of vitronectin. This evidence indicates that PAI-1 alters the adhesive functions of vitronectin by converting the protein via the higher order complex to a self-associated, multivalent species that is functionally distinct from the abundant monomeric form found in the circulation.The interactions that occur between cellular receptors and proteins that constitute the extracellular matrix are vital to physiological control of processes like cell adhesion and pericellular proteolysis. Events that alter these interactions can be deleterious, leading to pathological sequelae such as improper wound healing and tumor cell migration or metastasis. For example, components of the humoral response system known as fibrinolysis, which play a role in modulating various cellbinding properties of the extracellular matrix, can be exploited by cancerous cells. By altering the content and activity of proteins related to fibrinolysis, abnormally developing cells can acquire the ability to exit residing tissues and eventually invade and metastasize. An example involves the main regulator of fibrinolysis, PAI-1, 1 in which increased levels of the protein in plasma correlate with the presence of malignant ovarian cancer and higher incidence of disease (1).PAI-1 is a member of the serpin family and represents a key regulatory protein in proteolytic processes responsible for tissue remodeling and tumor metastasis. This property is owed to the fact that PAI-1 is the main inhibitor of both plasminogen activators, uPA and tPA. Interesting features of PAI-1 include its structural lability and the propensity it exhibits to spontaneously adopt a more stable, but inactive conformation. This feature of PAI-1 is unique among the serpin family, with active PAI-1 exhibiting a half-life of ϳ90 min (2). In the body, however, this transition of PAI-1 into an inactive for...

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The Significance of Colocalization of Plasminogen Activator Inhibitor-1 and Vitronectin in Hepatic Fibrosis

Abstract: These findings suggest that VN and PAI-1 are related to the active form of TGF-beta and that it is possible that the plasmin cascade is present in the human liver.

Cited by 16 publications

References 29 publications

Metals affect the structure and activity of human plasminogen activator inhibitor‐1. I. Modulation of stability and protease inhibition

Metals affect the structure and activity of human plasminogen activator inhibitor‐1. I. Modulation of stability and protease inhibition

Cross-Talk between Human Mast Cells and Bronchial Epithelial Cells in Plasminogen Activator Inhibitor-1 Production via Transforming Growth Factor-β1

Plasminogen Activator Inhibitor Type 1 Promotes the Self-association of Vitronectin into Complexes Exhibiting Altered Incorporation into the Extracellular Matrix

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