Uric Acid Induces a Proatherothrombotic Phenotype in Human Endothelial Cells by Imbalancing the Tissue Factor/Tissue Factor Pathway Inhibitor Pathway

Cimmino G. Conte S. Marra L. Morello A. Morello M. De Rosa G. Pepe M. Sugraliyev A. Golino P. Cirillo P.
1 January 2023 Georg Thieme Verlag

Thrombosis and Haemostasis
2023 #123 Issue 1 64 - 75 pp.

Background Several evidence show that elevated plasma levels of uric acid (UA) are associated with the increased risk of developing atherothrombotic cardiovascular events. Hyperuricemia is a risk factor for endothelial dysfunction (ED). ED is involved in the pathophysiology of atherothrombosis since dysfunctional cells lose their physiological, antithrombotic properties. We have investigated whether UA might promote ED by modulating the tissue factor (TF)/TF pathway inhibitor (TFPI) balance by finally changing the antithrombotic characteristics of endothelial cells. Methods Human umbilical vein endothelial cells were incubated with increasing doses of UA (up to 9 mg/dL). TF gene and protein expressions were evaluated by real-time polymerase chain reaction (PCR) andWestern blot. Surface expression and procoagulant activity were assessed by FACS (fluorescence activated cell sorting) analysis and coagulation assay. ThemRNA and protein levels of TFPI weremeasured by real-time PCR andWestern blot. The roles of inflammasome and nuclear factor-?B (NF-?B) as possible mechanism(s) of action of the UA on TF/TFPI balance were also investigated. Results UA significantly increased TF gene and protein levels, surface expression, and procoagulant activity. In parallel, TFPI levels were significantly reduced. The NF-?B pathways appeared to be involved in modulating these phenomena. Additionally, inflammasome might also play a role. Conclusion The present in vitro study shows that one of the mechanisms by which high levels of UA contribute to ED might be the imbalance between TF/TFPI levels in endothelial cells, shifting them to a nonphysiological, prothrombotic phenotype. These UA effects might hypothetically explain, at least in part, the relationship observed between elevated plasma levels of UA and cardiovascular events.

inflammation , TFPI , tissue factor , uric acid

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Section of Cardiology, Department of Translational Medical Sciences, University of Campania, Luigi Vanvitelli, Naples, Italy
SC Cell Biology and Biotherapy, Istituto Nazionale Tumori IRCCS, Fondazione G. Pascale, Naples, Italy
Biochemical Unit, Antonio Cardarelli Hospital, Azienda Sanitaria Regionale Molise, Campobasso, Italy
Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, Bari, Italy
Department of Internal Disease, Kazakh National Medical University, Almaty, Kazakhstan

Section of Cardiology
SC Cell Biology and Biotherapy
Biochemical Unit
Division of Cardiology
Cardiovascular Diseases Section
Department of Internal Disease

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