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Targeting Vascular Tissue Factor Expression: Pathophysiology and Clinical Implications


Holy, E W. Targeting Vascular Tissue Factor Expression: Pathophysiology and Clinical Implications. 2012, University of Zurich, Faculty of Science.

Abstract

Arterial thrombosis is the critical event in acute vascular syndromes such as unstable angina pectoris, myocardial infarction, peripheral ischemia, and stroke. The fate of a forming thrombus is determined by the balance between pro-thrombotic mediators such as tissue factor (TF) and plasminogen activator inhibitor type 1 (PAI- 1), and anti-thrombotic factors like tissue factor pathway inhibitor (TFPI) or tissue plasminogen activator (tPA). TF, a 263-residue membrane-bound glycoprotein, is a key protein for the activation of coagulation; it binds activated factor VII (FVIIa), which in turn activates factor X, ultimately leading to thrombin formation. TF expression is upregulated by several mediators such as tumor necrosis factor-α (TNF-α) or thrombin and can be detected in a variety of cell types in atheromatous plaques. In addition to the classical antithrombotic agents, drugs targeting TF and the TF:FVIIa complex have recently been introduced, since inhibiting the initiation phase may prevent thrombus formation more efficiently. Moreover, considering the nonhemostatic properties of the TF:VIIa complex, inhibition of TF may also interfere with the promigratory and proproliferative effects of TF. In the present study we characterized the effect of compounds, which have been proposed to exert cardioprotective properties on the expression of prothrombotic markers in the vessel wall, in particular TF expression, by the use of cellular and in vivo models. In the first project, we demonstrated that alpha-linolenic acid (ALA), a plantderived n-3 fatty acid, potently inhibits TF expression and activity in vascular smooth muscle and endothelial cells. This effect was mediated at the transcriptional level by inhibition of the mitogen activated protein-kinase pathways and the transcription nuclear factor kappa-light-chain-enhancer of activated B-cells (NFkappaB or NFkB). In line with this observation mice fed an ALA-rich diet for 2 weeks suffered a significantly delayed thrombotic occlusion following photochemical vessel wall injury as compared to controls. Moreover we could demonstrate that this antithrombotic effect was partially mediated by an inhibitory effect of ALA on platelet activation and aggregation. Hence, ALA may represent an attractive nutritional intervention with direct dual anti-thrombotic effects. Epigallocatechin-3-gallate (EGCG) is a polyphenol found in green tea and experimental as well epidemiological studies revealed important cardioprotective properties of ECGC. Recently EGCG has been characterized as a ligand for the 67 kDa laminin receptor (67LR). In the second project we demonstrated that activation of the 67LR by laminin or EGCG inhibits cytokine induced TF expression in endothelial cells via the c-Jun N-terminal kinases 1 and 2, and identified 67LR as a potential target for the development of novel anti-thrombotic therapies. Aim of the third project was to investigate whether the natural lipid lowering drug berberine (BBR), similar to statins, exerts pleiotropic effects on endothelial tissue factor (TF) expression. We showed that BBR, at physiologically relevant concentrations, enhances TF expression and in parallel decreases TFPI expression both in human endothelial cells and in arteries of ApoE-/- mice. Analysis of the mechanisms demonstrated that BBR enhanced cytokine induced TF expression through a posttranscriptional mechanism involving stabilization of TF mRNA. BBR may therefore favor the development of arterial thrombosis, in particular in patients with atherosclerotic lesions since inflammatory environments are often encountered under these conditions, and its use in clinical practice should be considered with caution until large-scale clinical trials have evaluated its safety. Finally, in the last project we characterized the role of the phosphatidylinositol-3 kinase (PI3K) signaling pathway in the vasculature. The PI3K controls major cellular processes such as cell cycle, proliferation and differentiation. In the vasculature,p110α is the predominant PI3k isoform expressed in endothelial and vascular smooth muscle cells. This study was designed to address the role of p110α in endothelial cell and vascular smooth muscle cell proliferation, migration, and activation, which are critically involved in the pathogenesis of atherothrombosis. We demonstrated that inhibition of p110α differentially regulates smooth muscle and endothelial cells. In addition to its potent antiproliferative and antimigratory effects on smooth muscle cells, targeting p110α also inhibits the expression of prothrombotic markers on endothelial such as TF and PAI-1. Considering that specific targeting of p110 isoforms is currently evaluated in different areas of modern medicine, we propose local p110α inhibition as a novel antithrombotic strategy in particular in the context of drug eluting stent design, in order to prevent restenosis without adding the risk of enhanced thrombogenicity. In summary this study supports the concept that modulation of TF expression in the vasculature represents an attractive target in preventing arterial thrombus formation associated with the development of cardiovascular events and proposes new strategies to inhibit TF expression. Hence, this work may contribute to the development of new potent antithrombotic drugs.

Abstract

Arterial thrombosis is the critical event in acute vascular syndromes such as unstable angina pectoris, myocardial infarction, peripheral ischemia, and stroke. The fate of a forming thrombus is determined by the balance between pro-thrombotic mediators such as tissue factor (TF) and plasminogen activator inhibitor type 1 (PAI- 1), and anti-thrombotic factors like tissue factor pathway inhibitor (TFPI) or tissue plasminogen activator (tPA). TF, a 263-residue membrane-bound glycoprotein, is a key protein for the activation of coagulation; it binds activated factor VII (FVIIa), which in turn activates factor X, ultimately leading to thrombin formation. TF expression is upregulated by several mediators such as tumor necrosis factor-α (TNF-α) or thrombin and can be detected in a variety of cell types in atheromatous plaques. In addition to the classical antithrombotic agents, drugs targeting TF and the TF:FVIIa complex have recently been introduced, since inhibiting the initiation phase may prevent thrombus formation more efficiently. Moreover, considering the nonhemostatic properties of the TF:VIIa complex, inhibition of TF may also interfere with the promigratory and proproliferative effects of TF. In the present study we characterized the effect of compounds, which have been proposed to exert cardioprotective properties on the expression of prothrombotic markers in the vessel wall, in particular TF expression, by the use of cellular and in vivo models. In the first project, we demonstrated that alpha-linolenic acid (ALA), a plantderived n-3 fatty acid, potently inhibits TF expression and activity in vascular smooth muscle and endothelial cells. This effect was mediated at the transcriptional level by inhibition of the mitogen activated protein-kinase pathways and the transcription nuclear factor kappa-light-chain-enhancer of activated B-cells (NFkappaB or NFkB). In line with this observation mice fed an ALA-rich diet for 2 weeks suffered a significantly delayed thrombotic occlusion following photochemical vessel wall injury as compared to controls. Moreover we could demonstrate that this antithrombotic effect was partially mediated by an inhibitory effect of ALA on platelet activation and aggregation. Hence, ALA may represent an attractive nutritional intervention with direct dual anti-thrombotic effects. Epigallocatechin-3-gallate (EGCG) is a polyphenol found in green tea and experimental as well epidemiological studies revealed important cardioprotective properties of ECGC. Recently EGCG has been characterized as a ligand for the 67 kDa laminin receptor (67LR). In the second project we demonstrated that activation of the 67LR by laminin or EGCG inhibits cytokine induced TF expression in endothelial cells via the c-Jun N-terminal kinases 1 and 2, and identified 67LR as a potential target for the development of novel anti-thrombotic therapies. Aim of the third project was to investigate whether the natural lipid lowering drug berberine (BBR), similar to statins, exerts pleiotropic effects on endothelial tissue factor (TF) expression. We showed that BBR, at physiologically relevant concentrations, enhances TF expression and in parallel decreases TFPI expression both in human endothelial cells and in arteries of ApoE-/- mice. Analysis of the mechanisms demonstrated that BBR enhanced cytokine induced TF expression through a posttranscriptional mechanism involving stabilization of TF mRNA. BBR may therefore favor the development of arterial thrombosis, in particular in patients with atherosclerotic lesions since inflammatory environments are often encountered under these conditions, and its use in clinical practice should be considered with caution until large-scale clinical trials have evaluated its safety. Finally, in the last project we characterized the role of the phosphatidylinositol-3 kinase (PI3K) signaling pathway in the vasculature. The PI3K controls major cellular processes such as cell cycle, proliferation and differentiation. In the vasculature,p110α is the predominant PI3k isoform expressed in endothelial and vascular smooth muscle cells. This study was designed to address the role of p110α in endothelial cell and vascular smooth muscle cell proliferation, migration, and activation, which are critically involved in the pathogenesis of atherothrombosis. We demonstrated that inhibition of p110α differentially regulates smooth muscle and endothelial cells. In addition to its potent antiproliferative and antimigratory effects on smooth muscle cells, targeting p110α also inhibits the expression of prothrombotic markers on endothelial such as TF and PAI-1. Considering that specific targeting of p110 isoforms is currently evaluated in different areas of modern medicine, we propose local p110α inhibition as a novel antithrombotic strategy in particular in the context of drug eluting stent design, in order to prevent restenosis without adding the risk of enhanced thrombogenicity. In summary this study supports the concept that modulation of TF expression in the vasculature represents an attractive target in preventing arterial thrombus formation associated with the development of cardiovascular events and proposes new strategies to inhibit TF expression. Hence, this work may contribute to the development of new potent antithrombotic drugs.

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Additional indexing

Item Type:Dissertation
Referees:Wenger R H, Tanner F C, Resink Therese
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2012
Deposited On:17 Jan 2013 11:55
Last Modified:05 Apr 2016 16:21

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