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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.


 

  • References

  • 1 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874.
    CrossrefPubMedSearch in Google Scholar
  • 2 Corti R, Hutter R, Badimon JJ. et al. Evolving concepts in the triad of atherosclerosis, inflammation and thrombosis. J Thromb Thrombolysis 2004; 17: 35-44.
    CrossrefPubMedSearch in Google Scholar
  • 3 Owens 3rd AP, Mackman N. Tissue factor and thrombosis: The clot starts here. Thromb Haemost 2010; 104: 432-439.
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Steffel J, Luscher TF, Tanner FC. Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications. Circulation 2006; 113: 722-731.
    CrossrefPubMedSearch in Google Scholar
  • 5 Roque M, Reis ED, Fuster V. et al. Inhibition of tissue factor reduces thrombus formation and intimal hyperplasia after porcine coronary angioplasty. J Am Coll Cardiol 2000; 36: 2303-2310.
    CrossrefPubMedSearch in Google Scholar
  • 6 Happonen P, Voutilainen S, Salonen JT. Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men. J Nutr 2004; 134: 2381-2386.
    CrossrefPubMedSearch in Google Scholar
  • 7 Woodward M, Tunstall-Pedoe H. Coffee and tea consumption in the Scottish Heart Health Study follow up: conflicting relations with coronary risk factors, coronary disease, and all cause mortality. J Epidemiol Community Health 1999; 53: 481-487.
    CrossrefPubMedSearch in Google Scholar
  • 8 LaCroix AZ, Mead LA, Liang KY. et al. Coffee consumption and the incidence of coronary heart disease. N Engl J Med 1986; 315: 977-982.
    CrossrefPubMedSearch in Google Scholar
  • 9 Baylin A, Hernandez-Diaz S, Kabagambe EK. et al. Transient exposure to coffee as a trigger of a first nonfatal myocardial infarction. Epidemiology 2006; 17: 506-511.
    CrossrefPubMedSearch in Google Scholar
  • 10 Jee SH, He J, Appel LJ. et al. Coffee consumption and serum lipids: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol 2001; 153: 353-362.
    CrossrefPubMedSearch in Google Scholar
  • 11 Jacques PF, Bostom AG, Wilson PW. et al. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 2001; 73: 613-621.
    CrossrefPubMedSearch in Google Scholar
  • 12 Ammon HP, Bieck PR, Mandalaz D. et al. Adaptation of blood pressure to continuous heavy coffee drinking in young volunteers. A double-blind crossover study. Br J Clin Pharmacol 1983; 15: 701-706.
    PubMedSearch in Google Scholar
  • 13 Jick H, Miettinen OS, Neff RK. et al. Coffee and myocardial infarction. N Engl J Med 1973; 289: 63-67.
    CrossrefPubMedSearch in Google Scholar
  • 14 Foukas LC, Daniele N, Ktori C. et al. Direct effects of caffeine and theophylline on p110 delta and other phosphoinositide 3-kinases. Differential effects on lipid kinase and protein kinase activities. J Biol Chem 2002; 277: 37124-37130.
    PubMedSearch in Google Scholar
  • 15 Huang ZL, Qu WM, Eguchi N. et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci 2005; 08: 858-859.
    CrossrefPubMedSearch in Google Scholar
  • 16 Viswambharan H, Ming XF, Zhu S. et al. Reconstituted high-density lipoprotein inhibits thrombin-induced endothelial tissue factor expression through inhibition of RhoA and stimulation of phosphatidylinositol 3-kinase but not Akt/ endothelial nitric oxide synthase. Circ Res 2004; 94: 918-925.
    CrossrefPubMedSearch in Google Scholar
  • 17 Steffel J, Latini RA, Akhmedov A. et al. Rapamycin, but not FK-506, increases endothelial tissue factor expression: implications for drug-eluting stent design. Circulation 2005; 112: 2002-2011.
    CrossrefPubMedSearch in Google Scholar
  • 18 Schabbauer G, Tencati M, Pedersen B. et al. PI3K-Akt pathway suppresses coagulation and inflammation in endotoxemic mice. ArteriosclerThrombVascBiol 2004; 24: 1963-1969.
    PubMedSearch in Google Scholar
  • 19 Fougerat A, Gayral S, Gourdy P. et al. Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes. Circulation 2008; 117: 1310-1317.
    CrossrefPubMedSearch in Google Scholar
  • 20 Jackson SP, Schoenwaelder SM, Goncalves I. et al. PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med 2005; 11: 507-514.
    CrossrefPubMedSearch in Google Scholar
  • 21 Stahli BE, Camici GG, Steffel J. et al. Paclitaxel enhances thrombin-induced endothelial tissue factor expression via c-Jun terminal NH2 kinase activation. Circ Res 2006; 99: 149-155.
    CrossrefPubMedSearch in Google Scholar
  • 22 Steffel J, Akhmedov A, Greutert H. et al. Histamine induces tissue factor expression: implications for acute coronary syndromes. Circulation 2005; 112: 341-349.
    CrossrefPubMedSearch in Google Scholar
  • 23 Camici GG, Steffel J, Akhmedov A. et al. Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Circulation 2006; 114: 1512-1521.
    CrossrefPubMedSearch in Google Scholar
  • 24 Ming XF, Barandier C, Viswambharan H. et al. Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway: implications for atherosclerotic endothelial dysfunction. Circulation 2004; 110: 3708-3714.
    CrossrefPubMedSearch in Google Scholar
  • 25 Sudano I, Binggeli C, Spieker L. et al. Cardiovascular effects of coffee: is it a risk factor?. Prog Cardiovasc Nurs 2005; 20: 65-69.
    CrossrefPubMedSearch in Google Scholar
  • 26 Fredholm BB, Battig K, Holmen J. et al. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 1999; 51: 83-133.
    PubMedSearch in Google Scholar
  • 27 Mandel HG. Update on caffeine consumption, disposition and action. Food ChemToxicol 2002; 40: 1231-1234.
    CrossrefPubMedSearch in Google Scholar
  • 28 Pedersen B, Holscher T, Sato Y. et al. A balance between tissue factor and tissue factor pathway inhibitor is required for embryonic development and hemostasis in adult mice. Blood 2005; 105: 2777-2782.
    CrossrefPubMedSearch in Google Scholar
  • 29 Pearson JD, Gordon JL. Vascular endothelial and smooth muscle cells in culture selectively release adenine nucleotides. Nature 1979; 281: 384-386.
    CrossrefPubMedSearch in Google Scholar
  • 30 Engler RL. Adenosine. The signal of life?. Circulation 1991; 84: 951-954.
    PubMedSearch in Google Scholar
  • 31 Ely SW, Berne RM. Protective effects of adenosine in myocardial ischemia. Circulation 1992; 85: 893-904.
    CrossrefPubMedSearch in Google Scholar
  • 32 Downey JM, Liu GS, Thornton JD. Adenosine and the anti-infarct effects of preconditioning. CardiovascRes 1993; 27: 3-8.
    PubMedSearch in Google Scholar
  • 33 Fredholm BB. Astra Award Lecture. Adenosine, adenosine receptors and the actions of caffeine. Pharmacol Toxicol 1995; 76: 93-101.
    PubMedSearch in Google Scholar
  • 34 White PJ, Nguyen TT. Chronic caffeine treatment causes changes in cardiac adenosine receptor function in rats. Pharmacology 2002; 65: 129-135.
    CrossrefPubMedSearch in Google Scholar
  • 35 Aqel RA, Zoghbi GJ, Trimm JR. et al. Effect of caffeine administered intravenously on intracoronary-administered adenosine-induced coronary hemodynamics in patients with coronary artery disease. Am J Cardiol 2004; 93: 343-346.
    CrossrefPubMedSearch in Google Scholar
  • 36 Deguchi H, Takeya H, Urano H. et al. Adenosine regulates tissue factor expression on endothelial cells. ThrombRes 1998; 91: 57-64.
    PubMedSearch in Google Scholar
  • 37 Kim YH, Choi KH, Park JW. et al. LY294002 inhibits LPS-induced NO production through a inhibition of NF-kappaB activation: independent mechanism of phosphatidylinositol 3-kinase. Immunol Lett 2005; 99: 45-50.
    CrossrefPubMedSearch in Google Scholar
  • 38 Ojaniemi M, Glumoff V, Harju K. et al. Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated cytokine expression in mouse macrophages. Eur J Immunol 2003; 33: 597-605.
    CrossrefPubMedSearch in Google Scholar
  • 39 Wilson PW, Garrison RJ, Kannel WB. et al. Is coffee consumption a contributor to cardiovascular disease?. Insights from the Framingham Study. Arch Intern Med 1989; 149: 1169-1172.
    PubMedSearch in Google Scholar