Transcellular Signaling and Pharmacological Modulation of Thrombin-Induced Production of Plasminogen Activator Inhibitor-1 in Vascular Smooth Muscle Cells

Shen, Garry X.; Ren, Shiyan; Fenton, John W.

doi:10.1055/s-2007-995834

Cited by 11 publications

(5 citation statements)

References 24 publications

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“…In line with this study, we and othershaveshown that thrombin is able to enhance PA I-1 mRNAand protein levels in pulmonary artery and other smooth muscle cells (18,28,33,34) although the involvement of PA R-1i nP AI-1 regulation has not been described so farinP ASMC.However,inpericytes, butnot in endothelial cells,thrombin increased the secretion of PA I-1 by activation of PA R-1 (35) suggesting that PA R-1regulation of PA I-1 levels is cell-type specific.…”

Section: Rac-1 Regulatesp Ai-1supporting

confidence: 90%

Rac-1 promotes pulmonary artery smooth muscle cell proliferation by upregulation of plasminogen activator inhibitor-1: Role of NFκB-dependent hypoxia-inducible factor-1α transcription

Diebold¹,

Djordjevic²,

Hess³

et al. 2008

Thromb Haemost

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Pulmonary vascular remodeling is commonly associated with pulmonary hypertension and is characterized by media thickening and disordered cellular proliferation, often accompanied by fibrin deposition and thrombosis in situ. However, the signaling pathways linking these different processes are not well understood. Since the GTPase Rac-1 has been suggested to act as a signaling relay in various cell types we investigated whether Rac-1 could be the link between thrombin signaling, plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis and promotes fibrin deposition, and proliferation of pulmonary artery smooth muscle cells (PASMC). Exposure to thrombin enhanced the levels of Rac-1 protein and increased PAI-1 mRNA and protein expression in dependence of the thrombin receptor PAR-1. Expression of dominant-negative Rac-1 (RacT17N) prevented thrombin-induced PAI-1 expression whereas constitutively active RacG12V enhanced PAI-1 levels. In the presence of RacT17N thrombin-induced PAI-1 promoter activity was abrogated whereas RacG12V increased PAI-1 promoter activity, and this response was essentially dependent on the transcription factor hypoxia-inducible factor-1 (HIF-1). Subsequently, RacG12V not only increased HIF transcriptional activity but also HIF-1alpha protein and mRNA levels, whereas RacT17N prevented these responses elicited by thrombin. In line, RacG12V enhanced HIF-1alpha promoter activity, and this response was dependent on nuclear factor-kappaB (NFkappaB) binding to the HIF-1alpha promoter. Finally, upregulation of PAI-1 by Rac-1 and HIF-1 was essential for thrombin-stimulated proliferation of PASMC. These findings indicate that Rac-1 is an important mediator of thrombin signaling and may contribute to pulmonary vascular remodeling via HIF-1-dependent upregulation of PAI-1 leading to enhanced proliferation of PASMC.

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Section: Rac-1 Regulatesp Ai-1supporting

confidence: 90%

Rac-1 promotes pulmonary artery smooth muscle cell proliferation by upregulation of plasminogen activator inhibitor-1: Role of NFκB-dependent hypoxia-inducible factor-1α transcription

Diebold¹,

Djordjevic²,

Hess³

et al. 2008

Thromb Haemost

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“…Thus, similar to endothelial macroparticles, 22 mast cell-derived exosomes have procoagulant properties. Because thrombin is known to stimulate PAI-1 synthesis, 29,30 mast cell-derived exosomes may provide a link for an intimate relationship between thrombin and PAI-1 generation under inflammatory conditions. Interestingly, the rate of in vitro thrombin generation is accelerated significantly by microparticles obtained from the cultured HUVECs pretreated with PAI-1.…”

Section: Discussionmentioning

confidence: 99%

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

Al‐Nedawi

Szemraj

Cierniewski

2005

ATVB

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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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“…It is well recognized that the adenylyl cyclase-cAMP system has vasodilation effect through activation of cAMP-dependent protein kinase on vascular smooth muscle cells (Morgan et al, 1991). In vascular smooth muscle cells, it has been reported as follows: cAMP inhibits thrombin-induced cell growth (Rao and Runge, 1996), and plasminogen activator inhibitor-1 production (Shen et al, 1998), thrombin induces interleukin-6 expression through the cAMP response element (Tokunou et al, 2001a) and cAMP response element-binding protein mediates thrombin-induced cell proliferation (Tokunou et al, 2001b). Therefore, we next examined the adenylyl cyclase-cAMP system-effect on the thrombin-induced HSP27 phosphorylation and the mechanism behind the phosphorylation in A10 cells.…”

Section: Discussionmentioning

confidence: 99%

Akt regulates thrombin-induced HSP27 phosphorylation in aortic smooth muscle cells: Function at a point downstream from p38 MAP kinase

et al. 2005

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Transcellular Signaling and Pharmacological Modulation of Thrombin-Induced Production of Plasminogen Activator Inhibitor-1 in Vascular Smooth Muscle Cells

Cited by 11 publications

References 24 publications

Rac-1 promotes pulmonary artery smooth muscle cell proliferation by upregulation of plasminogen activator inhibitor-1: Role of NFκB-dependent hypoxia-inducible factor-1α transcription

Rac-1 promotes pulmonary artery smooth muscle cell proliferation by upregulation of plasminogen activator inhibitor-1: Role of NFκB-dependent hypoxia-inducible factor-1α transcription

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

Akt regulates thrombin-induced HSP27 phosphorylation in aortic smooth muscle cells: Function at a point downstream from p38 MAP kinase

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