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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
Published on: August 3, 2018
Laminin receptor activation inhibits endothelial tissue factor expression
Erik W Holy1, Simon F Stämpfli, Alexander Akhmedov
1Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland.
Journal of Molecular and Cellular Cardiology
|August 29, 2009
Summary
Epigallocatechin-3-gallate (EGCG) from green tea inhibits tissue factor (TF) expression in endothelial cells by activating the 67-kDa laminin receptor (67LR). This pathway targets JNK phosphorylation, offering potential anti-thrombotic therapies.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Pharmacology
Background:
- Tissue factor (TF) is a key initiator of arterial thrombosis.
- Epigallocatechin-3-gallate (EGCG), a green tea catechin, is a 67-kDa laminin receptor (67LR) ligand with cardioprotective properties.
Purpose of the Study:
- To investigate the role of 67LR in regulating endothelial TF expression.
- To explore the mechanism by which EGCG inhibits TF expression.
Main Methods:
- Immunofluorescence to detect 67LR in human aortic endothelial cells.
- Cell culture studies assessing TF expression and activity under varying conditions (laminin, fibronectin, EGCG, TNF-alpha, histamine).
- In vivo studies in C57BL6 mice, real-time PCR, promoter assays, and Western blotting to analyze TF expression, JNK pathway activation, and NFkB activation.
Main Results:
- Human aortic endothelial cells express 67LR.
- Laminin substrate reduced TNF-alpha-induced TF expression compared to fibronectin.
- EGCG dose-dependently inhibited TNF-alpha and histamine-induced TF expression and activity, with an 87% reduction at 30 microM.
- EGCG decreased TF expression transcriptionally by impairing JNK1/2 phosphorylation, an effect mimicked by a JNK inhibitor.
- 67LR blocking antibodies blocked EGCG's inhibitory effects on TF and JNK.
- EGCG did not affect tissue factor pathway inhibitor, VCAM-1, or NFkB activation.
Conclusions:
- 67LR activation inhibits endothelial TF expression by impairing JNK phosphorylation.
- EGCG's anti-thrombotic effects are mediated through the 67LR-JNK pathway.
- 67LR represents a potential therapeutic target for anti-thrombotic strategies.
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