Thromb Haemost 2023; 123(01): 064-075
DOI: 10.1055/a-1947-7716
Cellular Haemostasis and Platelets

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

Giovanni Cimmino
1   Section of Cardiology, Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli,” Naples, Italy
Stefano Conte
1   Section of Cardiology, Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli,” Naples, Italy
Laura Marra
2   SC Cell Biology and Biotherapy, Istituto Nazionale Tumori IRCCS, Fondazione G. Pascale, Naples, Italy
Andrea Morello
3   Biochemical Unit, Azienda Sanitaria Regionale Molise, Antonio Cardarelli Hospital, Campobasso, Italy
Mariarosaria Morello
4   Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples “Federico II,” Naples, Italy
Gennaro De Rosa
4   Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples “Federico II,” Naples, Italy
Martino Pepe
5   Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, Bari, Italy
Akhmetzhan Sugraliyev
6   Department of Internal Disease, Kazakh National Medical University, Almaty, Kazakhstan
Paolo Golino
1   Section of Cardiology, Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli,” Naples, Italy
Plinio Cirillo
4   Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples “Federico II,” Naples, Italy
› Author Affiliations
Funding This work was partially supported by V:ALERE Program 2019 (OMICS-ACS), University of Campania Luigi Vanvitelli. S.C. is supported by a grant from Ordine Italiano dei Biologi.


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) and Western blot. Surface expression and procoagulant activity were assessed by FACS (fluorescence activated cell sorting) analysis and coagulation assay. The mRNA and protein levels of TFPI were measured by real-time PCR and Western blot. The roles of inflammasome and nuclear factor-κB (NF-κB) 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-κB 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.

Publication History

Received: 08 March 2022

Accepted: 20 September 2022

Accepted Manuscript online:
20 September 2022

Article published online:
03 December 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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