title: Fructose induces prothrombotic phenotype in human endothelial cells : A new role for "added sugar" in cardio-metabolic risk.
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.
authors.affiliation: Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples, "Federico II", Naples, Italy. pcirillo@unina.it.
authors.forename: Plinio
authors.initials: P
authors.lastname: Cirillo
authors.affiliation: Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples, "Federico II", Naples, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Pellegrino
authors.affiliation: Division of Cardiology, Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, Naples, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Conte
authors.affiliation: Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples, "Federico II", Naples, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Maresca
authors.affiliation: Department of Molecular and Cellular Biology and Pathology, University of Naples, "Federico II", Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pacifico
authors.affiliation: Department of Molecular and Cellular Biology and Pathology, University of Naples, "Federico II", Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Leonardi
authors.affiliation: Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples, "Federico II", Naples, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
mesh_terms: D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D005632:Fructose / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D013549:Sweetening Agents / Q000009:adverse effects* / Q000494:pharmacology; D013925:Thromboplastin / Q000096:biosynthesis*; D013927:Thrombosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D013549:Sweetening Agents; D005632:Fructose; D013925:Thromboplastin
keywords: Atherothrombosis; Fructose; Tissue factor