Acute Phase Protein α1-Acid Glycoprotein Interacts with Plasminogen Activator Inhibitor Type 1 and Stabilizes Its Inhibitory Activity

Boncela, Joanna; Papiewska, Izabela; Fijałkowska, Iwona J.; Walkowiak, Bogdan; Cierniewski, Czesław S.

doi:10.1074/jbc.m104028200

Cited by 48 publications

(46 citation statements)

References 59 publications

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“…59 One could speculate that a-1-AGP delays thrombin generation by playing the same role with other coagulation inhibitors belonging to the serpin family. Conversely, a-1-AGP has been observed to shorten aPTT 60 and to contribute to the cellular initiation of coagulation by inducing monocyte expression of TF.…”

Section: Discussionmentioning

confidence: 99%

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential

Rocañín-Arjó

Cohen

Carcaillon

et al. 2014

Blood

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Key Points• Genetic variations at the ORM1 locus and concentrations of the encoded protein associate with thrombin generation.• These findings may guide the development of novel antithrombotic treatments.Thrombin, the major enzyme of the hemostatic system, is involved in biological processes associated with several human diseases. The capacity of a given individual to generate thrombin, called the thrombin generation potential (TGP), can be robustly measured in plasma and was shown to associate with thrombotic disorders. To investigate the genetic architecture underlying the interindividual TGP variability, we conducted a genome-wide association study in 2 discovery samples (N 5 1967) phenotyped for 3 TGP biomarkers, the endogenous thrombin potential, the peak height, and the lag time, and replicated the main findings in 2 independent studies (N 5 1254). We identified the ORM1 gene, coding for orosomucoid, as a novel locus associated with lag time variability, reflecting the initiation process of thrombin generation with a combined P value of P 5 7.1 3 10 215 for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P 5 8.7 3 10 210 ) and macrophages (P 5 3.2 3 10 23 ). In vitro functional experiments further demonstrated that supplementing normal plasma with increasing orosomucoid concentrations was associated with impaired thrombin generation. These results pave the way for novel mechanistic pathways and therapeutic perspectives in the etiology of thrombin-related disorders. (Blood. 2014;123(5):777-785)

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Section: Discussionmentioning

confidence: 99%

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential

Rocañín-Arjó

Cohen

Carcaillon

et al. 2014

Blood

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“…There was also a significant induction of ␣1-acid glycoprotein mRNA, which we recently described to form a complex with active PAI-1 and stabilize its activity. 23 The stimulating effect of exosomes on PAI-1 synthesis was further evidenced by measuring the amount of PAI-1 released to culture media from these cells, as determined by enzyme-linked immunosorbent assay (Figure 2A). To determine the molecular level at which PAI-1 expression can be regulated, we used a transient transfection approach to ask if exosome components can influence the transcription of the PAI-1 promoter.…”

Section: Induction Of Pai-1 Expression By Mast Cell-derived Exosomesmentioning

confidence: 99%

Mast Cell–Derived Exosomes Activate Endothelial Cells to Secrete Plasminogen Activator Inhibitor Type 1

Al‐Nedawi

Szemraj

Cierniewski

2005

ATVB

Self Cite

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Objective-Previous studies supported the contribution of exosomes to an acellular mode of communication, leading to intercellular transfer of molecules. In this study we provide evidence that mast cell-derived exosomes induce plasminogen activator inhibitor type 1 (PAI-1) expression in endothelial cells, detectable at the level of PAI-1 mRNA and protein synthesis. The stimulating effect was also measured at the level of PAI-1 promoter activity. Methods and Results-To identify components responsible for this activity, exosome proteins were separated by 2-dimensional PAGE, and protein spots were identified by microsequencing using electrospray (ISI-Q-TOF-Micromass) spectrometer. Components of 3 independent systems that can be involved in activation of endothelial cells, namely the prothrombinase complex, tumor necrosis factor-␣, and angiotensinogen precursors were identified. Procoagulant activity of exosomes was confirmed by a thrombin generation assay using a specific chromogenic substrate. Because the potential of mast cell-derived exosomes to induce PAI-1 expression was completely abolished by hirudin, thrombin generated on exosomes seems to be responsible for this activity. Conclusions-It can be concluded that mast cell-derived exosomes via significant upregulation of PAI-1 secretion from endothelial cells may provide feedback between the characteristically increased PAI-1 levels and procoagulant states, both observed in diverse syndromes manifesting as endothelial cell dysfunction. 5,6 or diabetes mellitus, 7 and contributes to procoagulant state in these and other conditions. Mast cells exert profound pleiotropic effects on immune cell reactions at inflammatory sites, where they are most likely influenced not only by the extracellular matrix and inflammatory mediators but also by the proximity of activated T lymphocytes. These cells have been implicated in 2 contrasting types of immune responses, the immediate hypersensitivity reactions associated with allergic phenomena and their acute activation by bacterial products during infection. 8 Mast cells are localized near blood vessels and are involved in the activation of the clotting system during inflammation to contain the injury and initiate tissue repair. This concept is supported by studies of the reverse passive Arthus reaction in mast cell-deficient mice cells, which showed that these cells contributed to the exudation of clotting factors resulting in fibrin deposition and enhancement of fibrin cross-linkage. 9,10 In view of the role of mast cells in deposition of fibrin during inflammation near the site of injury, the aim of the present study was to examine the effect of mast cells-derived exosomes on expression and secretion of plasminogen activator inhibitor type 1 (PAI-1) from endothelial cells. Because exocytosis is the process by which stimulation of plasma membrane receptors on secretory cells results in the release of proteins and/or peptides from the intracellular stores into the extracellular space, 11 we attempted to identify active compone...

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“…(Boncela et al, 2001); however, in that study AGP did not interfere with PAI-1 activity. As previously mentioned, serum AGP concentrations increase during late gestation in the pig and are highest at birth (Lampreave and Piñeiro, 1992), then rapidly decline postnatally Heegaard et al, 2013).…”

Section: Agp and Lipogenesis In Neonatal Pigsmentioning

confidence: 63%

α 1-acid glycoprotein inhibits lipogenesis in neonatal swine adipose tissue

Ramsay

Blomberg

Caperna

2016

Animal

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Serum α1-acid glycoprotein (AGP) is elevated during late gestation and at birth in the pig and rapidly declines postnatally. In contrast, the pig is born with minimal lipid stores in the adipose tissue, but rapidly accumulates lipid during the first week. The present study examined if AGP can affect adipose tissue metabolism in the neonatal pig. Isolated cell cultures or tissue explants were prepared from dorsal subcutaneous adipose tissue of preweaning piglets. Porcine AGP was used at concentrations of 0, 100, 1000 and 5000 ng/ml medium in 24 h incubations. AGP reduced the messenger RNA (mRNA) abundance of the lipogenic enzymes, malic enzyme (ME), fatty acid synthase and acetyl coA carboxylase by at least 40% ( P < 0.001). The activity of ME and citrate lyase were also reduced by AGP ( P < 0.05). Glucose oxidation was reduced by treatment with 5000 ng AGP/ml medium ( P < 0.05). The 14 C-glucose incorporation into fatty acids was reduced by~25% by AGP treatment for 24 h with 1000 ng AGP/ml medium ( P < 0.05). The decrease in glucose metabolism by AGP appears to function through an inhibition in insulin-mediated glucose oxidation and incorporation into fatty acids. This was supported by the analysis of the mRNA abundance for sterol regulatory element-binding protein (SREBP), carbohydrate regulatory element-binding protein (ChREBP) and insulin receptor substrate 1 (IRS1), which all demonstrated reductions of at least 23% in response to AGP treatment ( P < 0.05). These data demonstrate an overall suppression of lipogenesis due to AGP inhibition of lipogenic gene expression in vitro, which the metabolic data and SREBP, ChREBP and IRS1 gene expression analysis suggest is through an inhibition in insulin-mediated events. Second, these data suggest that AGP may contribute to limiting lipogenesis within adipose tissue during the perinatal period, as AGP levels are highest for any serum protein at birth.

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Acute Phase Protein α1-Acid Glycoprotein Interacts with Plasminogen Activator Inhibitor Type 1 and Stabilizes Its Inhibitory Activity

Cited by 48 publications

References 59 publications

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential

Mast Cell–Derived Exosomes Activate Endothelial Cells to Secrete Plasminogen Activator Inhibitor Type 1

α 1-acid glycoprotein inhibits lipogenesis in neonatal swine adipose tissue

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