Abstract
Intake of large amounts of added sweeteners has been associated with the pathogenesis of cardiometabolic risk. Several studies have shown that fructose increases the cardiovascular risk by modulating endothelial dysfunction and promoting atherosclerosis. Recently, a potential role for fructose in cardiovascular thrombosis has been suggested but with controversial results. Tissue factor (TF) plays a pivotal role in the pathophysiology of cardiovascular thrombosis by triggering the formation of intracoronary thrombi following endothelial injury. This study investigates the effects of fructose, in a concentration range usually observed in the plasma of patients with increased cardiovascular risk, on TF in human umbilical endothelial cells (HUVECs). Cells were stimulated with increasing concentrations of fructose (0.25, 1 and 2.5 mM) and then processed to evaluate TF-mRNA levels by real-time PCR as well as TF expression/activity by FACS analysis and procoagulant activity. Finally, a potential molecular pathway involved in modulating this phenomenon was investigated. We demonstrate that fructose induces transcription of mRNA for TF. In addition, we show that this monosaccharide promotes surface expression of TF that is functionally active. Fructose effects on TF appear modulated by the oxygen free radicals through activation of the transcription factor NF-κB since superoxide dismutase and NF-κB inhibitors suppressed TF expression. Data of the present study, although in vitro, indicate that fructose, besides promoting atherosclerosis, induces a prothrombotic phenotype in HUVECs, thus indicating one the mechanism(s) by which this sweetener might increase cardiometabolic risk.
Similar content being viewed by others
References
Johnson RK, Appel LJ, Brands M, et al; American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity and Metabolism and the Council on Epidemiology and Prevention (2009) Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association. Circulation 120:1011–1020
Hubert HB, Feinleib M, McNamara PM et al (1983) Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 67:968–977
Sowers JR (2003) Obesity as a cardiovascular risk factor. Am J Med 115:37–41
Tappy L, Le KA (2010) Metabolic effects of fructose and the world wide increase in obesity. Physiol Rev 90:23–46
Khitan Z, Kim DH (2013) Fructose: a key factor in the development of metabolic syndrome and hypertension. J Nutr Metab 2013:682673
Cozma AI, Sievenpiper JL, de Souza RJ et al (2012) Effects of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials. Diabetes Care 35:1611–1620
Bray GA (2012) Fructose and risk of cardiometabolic disease. Curr Atheroscler Rep 14:570–578
Beck-Nielsen H, Pedersen O, Lindskoc HO (1980) Impaired cellular insulin binding and insulin sensitivity induced by high-fructose feeding in normal subjects. Am J Clin Nutr 33:273–278
Ross R (1999) Atherosclerosis: an inflammatory disease. N Engl J Med 340:115–126
Price DT, Loscalzo J (1999) Cellular adhesion molecules and atherogenesis. Am J Med 107:85–97
Simionescu M (2007) Implications of early structural-functional changes in the endothelium for vascular disease. Arterioscler Thromb Vasc Biol 27(2):266–274
Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874
O’Brien KD, McDonald TO, Chait A et al (1996) Neovascular expression of E-selectin, intercellular adhesion molecule-1 and vascular adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation 93:672–682
Glushakova O, Kosugi T, Roncal C et al (2008) Fructose induces the inflammatory molecule ICAM-1 in endothelial cells. J Am Soc Nephrol 19:1712–1720
Toschi V, Gallo R, Lettino M et al (1997) Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 95(3):594–599
Ragni M, Cirillo P, Pascucci I et al (1996) A monoclonal antibody against tissue factor shortens tissue-plasminogen activator lysis time and prevents reocclusion in a rabbit model of carotid artery thrombosis. Circulation 93:1913–1920
Bierhaus A, Chen J, Liliensiek B et al (2000) LPS and cytokine activated endothelium. Semin Thromb Hemost 26:571–587
Golino P, Ragni M, Cirillo P et al (1996) Effects of tissue factor induced by oxygen free radicals on coronary flow during reperfusion. Nat Med 2:35–40
Cirillo P, Golino P, Calabro P et al (2005) C-Reactive Protein induces Tissue Factor expression and promotes smooth muscle and endothelial cell proliferation. Cardiovasc Res 68(1):47–55
Cirillo P, Angri V, De Rosa S et al (2010) Pro athero-thrombotic effects of leptin in human coronary endothelial cells. Thromb Haemost 103(5):1065–1075
Cirillo P, Ziviello F, Pellegrino G et al (2015) The adipokine apelin-13 induces expression of prothrombotic tissue factor. Thromb Haemost 113(2):363–372
Rajwani A, Cubbon RM, Wheatcroft SB (2012) Cell specific insulin resistance: implications for atherosclerosis. Diabetes Metab Res Rev 28:627–634
Jindal A, Garcia-Touza M, Jindal N (2013) Jindal N et al Diabetic kidney disease and the cardiorenal syndrome: old disease, new perspectives. Endocrinol Metab Clin N Am 42:789–808
Tan HW, Xing SS, Bi XP, Li L et al (2008) Felodipine attenuates vascular inflammation in a fructose-induced rat model of metabolic syndrome via the inhibition of NF-kB activation. Acta Pharmacol Sin 29:1051–1059
Eckel RH, Grundy SM, Zimmet PS (2005) The metabolic syndrome. Lancet 365:1415–1428
Berg AH, Scherer PE (2005) Adipose tissue, inflammation, and cardiovascular disease. Circ Res 96:939–949
Shinozaki K, Kashiwagi A, Nishio Y et al (1999) Abnormal biopterin metabolism is a major cause of impaired endothelium dependent relaxation through nitric/oxide/O2 imbalance in insulin resistant rat aorta. Diabetes 48:2437–2445
Gami AS, Witt BJ, Howard DE et al (2007) Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 49:403–414
Cox CL, Stanhope KL, Schwars JM et al (2011) Circulating concentrations of monocyte chemoattractant protein-1, plasminogen activator inhibitor-1 and soluble leukocyte adhesion molecule-1 in overweight/obese men and women consuming fructose- or glucose-sweetened beverages for 10 weeks. J Clin Endocrinol Metab 96:2034–2038
Dandona P, Aljada A, Chaudhuri A et al (2005) Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 111:1448–1454
Silbernagel G, Machann J, Haring HU et al (2014) Plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, e-selectin and C-reactive protein levels in response to 4-week very high-fructose or -glucose diet. Eur J Clin Nutr 68:97–100
Van De Craen B, Declerck PJ, Gils A (2012) The biochemistry, physiology and pathological roles of PAI-1 and the requirements for PAI-1 inhibition in vivo. Thromb Res 130(4):576–585
Meigs JB, Mittleman MA, Nathan DM et al (2000) Hyperinsulinemia, hyperglycemia and impaired hemostasis: the Framingham Offspring Study. JAMA 283:221–228
Pandolfi A, Cetrullo D, Polishick R et al (2001) Plasminogen activator inhibitor type 1 is increased in the arterial wall of type II diabetic subjects. Arterioscler Thrombo Vasc Biol 21:1378–1382
Van der Wouwer M, Collen D, Conway EM et al (2004) Thrombomodulin-protein C E-EPCR system. Integrated to regulate coagulation and inflammation. Arter Thromb Vasc Biol 24:1374–1383
Wang HJ, Huang HC, Chuang YC et al (2012) Modulation of tissue factor and thrombomodulin expression in human aortic endothelial cells incubated with high glucose. Acta Diabetol 49:125–130
Conway EM, Liu L, Nowakosky B et al (1994) Heat shock of vascular endothelial cells induces and up-regulatory transcriptional response of the thrombomodulin gene that is delayed in onset and does not attenuate. J Biol Chem 269:22804–22810
Barnes PJ, Karin M (1997) Nuclear factor-kappa B: a pivotal transcription factor in chronic inflammatory disease. N Engl J Med 336:1066–1071
Flohe L, Brigelius-Flohe R, Saliou C et al (1997) Redox regulation of NF-kappa B activation. Free Radic Biol Med 22:1115–1126
Oeth P, Parry GC, Mackman N (1997) Regulation of the tissue factor gene in human monocytic cells. Arterioscler Thromb Vasc Biol 17(2):365–374
Ritchie ME (1998) Nuclear Factor-κB is selectively and markedly activated in humans with unstable angina pectoris. Circulation 98:1707–1713
Wilson SH, Best PJ, Edwards WD et al (2002) Nuclear factor-kappaB immunoreactivity is present in human coronary plaque and enhanced in patients with unstable angina pectoris. Atherosclerosis 160:147–153
Carmeliet P, Mackman N, Moons L et al (1996) Role of tissue factor in embryonic blood vessels development. Nature 383:73–75
Bromberg ME, Sundaraman R, Homer RJ et al (1995) Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci USA 92:8205–8209
Randolph GJ, Luther T, Albrecht A et al (1998) Role of tissue factor in adhesion of mononuclear phagocytes to and trafficking through endothelium in vitro. Blood 2:4167–4177
Riewald M, Ruf W (2001) Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc Natl Acad Sci USA 98:7742–7747
Lima LG, Monteiro RQ (2013) Activation of blood coagulation in cancer: implication for tumor progression. Biosci Rep 33:e00064
Cirillo P, Calì G, Golino P et al (2004) Tissue factor binding of activated factor VII triggers smooth muscle cell proliferation via extracellular signal-regulated kinase activation. Circulation 109:2911–2916
van den Berg YW, Osanto S, Reitsma PH et al (2012) The relationship between tissue factor and cancer progression: insights from bench and bedside. Blood 119:924–932
Das UN (2015) Sucrose, fructose, glucose and their link to metabolic syndrome and cancer. Nutrition 31:249–257
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Additional information
This paper is dedicated to my daughter Camilla. Honey, “you are the sunshine of my life”.
Rights and permissions
About this article
Cite this article
Cirillo, P., Pellegrino, G., Conte, S. et al. Fructose induces prothrombotic phenotype in human endothelial cells. J Thromb Thrombolysis 40, 444–451 (2015). https://doi.org/10.1007/s11239-015-1243-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11239-015-1243-1