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Thromb Haemost 2012; 107(05): 884-894
DOI: 10.1160/TH11-09-0624
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Caffeine induces endothelial tissue factor expression via phosphatidylinositol 3-kinase inhibition

Cathérine Gebhard  
1   Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland
2   Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
3   Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland
,
Erik W. Holy  
1   Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland
2   Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
3   Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland
,
Giovanni G. Camici
1   Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland
2   Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Alexander Akhmedov
1   Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland
2   Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Simon F. Stämpfli
1   Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland
2   Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
3   Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland
,
Barbara E. Stähli
1   Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland
2   Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
3   Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland
,
Bettina von Rickenbach
1   Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland
2   Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Alexander Breitenstein
1   Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland
2   Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
3   Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland
,
Helen Greutert
1   Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland
2   Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Zhihong Yang
4   Vascular Biology, Department of Medicine, University of Fribourg, Fribourg, Switzerland
,
Thomas F. Lüscher
1   Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland
2   Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
3   Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland
,
Felix C. Tanner
1   Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland
2   Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
3   Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland
› Author Affiliations Financial support: This study was supported by the Swiss National Science Foundation (grant no. 3200B0–113328/1 to FCT, grant no. 3100–068118.02/1 to TFL and grant no. 310030_130500 to GGC), Bonizzi-Theler Foundation, Velux Foundation, Wolfermann Nägeli Foundation, and the Swiss Heart Foundation.
Further Information

Publication History

Received: 11 September 2011

Accepted after major revision: 16 January 2012

Publication Date:
25 November 2017 (online)

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Summary

Tissue factor (TF) is the key activator of coagulation and is involved in acute coronary syndromes. Caffeine is often reported to increase cardiovascular risk; however, its effect on cardiovascular morbidity and mortality is controversial. Hence, this study was designed to investigate the impact of caffeine on endothelial TF expression in vitro. Caffeine concentration-dependently enhanced TF protein expression and surface activity in human endothelial cells stimulated by tumour necrosis factor (TNF)-α or thrombin. Caffeine inhibited phosphatidylinositol 3-kinase (PI3K) activity and this effect was comparable to that of the known PI3K inhibitor LY294002. Consistently, treatment of endothelial cells with LY294002 enhanced TNF-α induced TF expression to a similar extent as caffeine, and adenoviral expression of the active PI3K mutant (p110) reversed the effect of both caffeine and LY294002 on TF expression. Caffeine and LY294002 increased DNA binding capacity of the transcription factor nuclear factor κB, whereas the activation pattern of mitogen-activated protein kinases (MAPK) remained unaltered. Luciferase reporter assay revealed a caffeine dependent activation of the TF promoter, and RT-PCR revealed a dose dependent increase in TF mRNA levels when stimulated with caffeine in the presence of TNF-α. In conclusion, caffeine enhances TNF-α-induced endothelial TF protein expression as well as surface activity by inhibition of PI3K signalling. Since the caffeine concentrations applied in the present study are within the plasma range measured in humans, our findings indicate that caffeine enhances the prothrombotic potential of endothelial cells and underscore the importance of PI3K in mediating these effects.

Keywords

Tissue factor / factor VII - signal transduction - coronary syndrome - endothelial cells - nutrition

These authors contributed equally to this work.


 

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