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DOI: 10.1055/a-1947-7716
Uric Acid Induces a Proatherothrombotic Phenotype in Human Endothelial Cells by Imbalancing the Tissue Factor/Tissue Factor Pathway Inhibitor Pathway
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.
Abstract
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.
Publikationsverlauf
Eingereicht: 08. März 2022
Angenommen: 20. September 2022
Accepted Manuscript online:
20. September 2022
Artikel online veröffentlicht:
03. Dezember 2022
© 2022. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
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References
- 1 Libby P. The changing landscape of atherosclerosis. Nature 2021; 592 (7855): 524-533
- 2 Gimbrone Jr MA, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 2016; 118 (04) 620-636
- 3 Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27 (11) 2292-2301
- 4 Grover SP, Mackman N. Tissue factor: an essential mediator of hemostasis and trigger of thrombosis. Arterioscler Thromb Vasc Biol 2018; 38 (04) 709-725
- 5 Jin Y, Fu J. Novel insights into the NLRP 3 inflammasome in atherosclerosis. J Am Heart Assoc 2019; 8 (12) e012219
- 6 Yu W, Cheng JD. Uric acid and cardiovascular disease: an update from molecular mechanism to clinical perspective. Front Pharmacol 2020; 11: 582680
- 7 Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999; 131 (01) 7-13
- 8 Johnson RJ, Kang DH, Feig D. et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?. Hypertension 2003; 41 (06) 1183-1190
- 9 Kuwabara M, Kuwabara R, Hisatome I. et al. “Metabolically Healthy” obesity and hyperuricemia increase risk for hypertension and diabetes: 5-year Japanese cohort study. Obesity (Silver Spring) 2017; 25 (11) 1997-2008
- 10 Kuwabara M, Niwa K, Hisatome I. et al. Asymptomatic hyperuricemia without comorbidities predicts cardiometabolic diseases: five-year Japanese cohort study. Hypertension 2017; 69 (06) 1036-1044
- 11 Kuwabara M, Borghi C, Cicero AFG. et al. Elevated serum uric acid increases risks for developing high LDL cholesterol and hypertriglyceridemia: a five-year cohort study in Japan. Int J Cardiol 2018; 261: 183-188
- 12 Kuwabara M, Niwa K, Nishihara S. et al. Hyperuricemia is an independent competing risk factor for atrial fibrillation. Int J Cardiol 2017; 231: 137-142
- 13 Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation 2002; 106 (02) 221-226
- 14 Rekhraj S, Gandy SJ, Szwejkowski BR. et al. High-dose allopurinol reduces left ventricular mass in patients with ischemic heart disease. J Am Coll Cardiol 2013; 61 (09) 926-932
- 15 Szwejkowski BR, Gandy SJ, Rekhraj S. et al. Allopurinol reduces left ventricular mass in patients with type 2 diabetes and left ventricular hypertrophy. J Am Coll Cardiol 2013; 62 (24) 2284-2293
- 16 Kimura Y, Tsukui D, Kono H. Uric acid in inflammation and the pathogenesis of atherosclerosis. Int J Mol Sci 2021; 22 (22) 12394
- 17 Zhi L, Yuzhang Z, Tianliang H, Hisatome I, Yamamoto T, Jidong C. High uric acid induces insulin resistance in cardiomyocytes in vitro and in vivo. PLoS One 2016; 11 (02) e0147737
- 18 Maruhashi T, Nakashima A, Soga J. et al. Hyperuricemia is independently associated with endothelial dysfunction in postmenopausal women but not in premenopausal women. BMJ Open 2013; 3 (11) e003659
- 19 Yan M, Chen K, He L, Li S, Huang D, Li J. Uric acid induces cardiomyocyte apoptosis via activation of calpain-1 and endoplasmic reticulum stress. Cell Physiol Biochem 2018; 45 (05) 2122-2135
- 20 Yu P, Zhang X, Liu N, Tang L, Peng C, Chen X. Pyroptosis: mechanisms and diseases. Signal Transduct Target Ther 2021; 6 (01) 128
- 21 Yang X, Gu J, Lv H. et al. Uric acid induced inflammatory responses in endothelial cells via up-regulating(pro)renin receptor. Biomed Pharmacother 2019; 109: 1163-1170
- 22 Liang WY, Zhu XY, Zhang JW, Feng XR, Wang YC, Liu ML. Uric acid promotes chemokine and adhesion molecule production in vascular endothelium via nuclear factor-kappa B signaling. Nutr Metab Cardiovasc Dis 2015; 25 (02) 187-194
- 23 Cimmino G, Morello A, Conte S. et al. Vitamin D inhibits tissue factor and CAMs expression in oxidized low-density lipoproteins-treated human endothelial cells by modulating NF-κB pathway. Eur J Pharmacol 2020; 885: 173422
- 24 Cimmino G, Cirillo P, Ragni M, Conte S, Uccello G, Golino P. Reactive oxygen species induce a procoagulant state in endothelial cells by inhibiting tissue factor pathway inhibitor. J Thromb Thrombolysis 2015; 40 (02) 186-192
- 25 Yao F, Jin Z, Zheng Z. et al. HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells. Cell Death Discov 2022; 8 (01) 112
- 26 Sugihara S, Hisatome I, Kuwabara M. et al. Depletion of uric acid due to SLC22A12 (URAT1) loss-of-function mutation causes endothelial dysfunction in hypouricemia. Circ J 2015; 79 (05) 1125-1132
- 27 Tassone EJ, Cimellaro A, Perticone M. et al. Uric acid impairs insulin signaling by promoting enpp1 binding to insulin receptor in human umbilical vein endothelial cells. Front Endocrinol (Lausanne) 2018; 9: 98
- 28 Oeth P, Parry GC, Mackman N. Regulation of the tissue factor gene in human monocytic cells. Role of AP-1, NF-kappa B/Rel, and Sp1 proteins in uninduced and lipopolysaccharide-induced expression. Arterioscler Thromb Vasc Biol 1997; 17 (02) 365-374
- 29 Cao Y, Zhou X, Liu H, Zhang Y, Yu X, Liu C. The NF-κB pathway: regulation of the instability of atherosclerotic plaques activated by Fg, Fb, and FDPs. Mol Cell Biochem 2013; 383 (1–2): 29-37
- 30 Xiao J, Zhang XL, Fu C. et al. Soluble uric acid increases NALP3 inflammasome and interleukin-1β expression in human primary renal proximal tubule epithelial cells through the Toll-like receptor 4-mediated pathway. Int J Mol Med 2015; 35 (05) 1347-1354
- 31 Cai W, Duan XM, Liu Y. et al. Uric acid induces endothelial dysfunction by activating the HMGB1/RAGE signaling pathway. BioMed Res Int 2017; 2017: 4391920
- 32 Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol 2016; 213: 8-14
- 33 Kanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ. The role of uric acid in the pathogenesis of human cardiovascular disease. Heart 2013; 99 (11) 759-766
- 34 Kanbay M, Afsar B, Covic A. Uric acid as a cardiometabolic risk factor: to be or not to be. Contrib Nephrol 2011; 171: 62-67
- 35 Katsiki N, Dimitriadis GD, Mikhailidis DP. Serum uric acid and diabetes: from pathophysiology to cardiovascular disease. Curr Pharm Des 2021; 27 (16) 1941-1951
- 36 Afsar B, Sag AA, Oztosun C. et al. The role of uric acid in mineral bone disorders in chronic kidney disease. J Nephrol 2019; 32 (05) 709-717
- 37 Jensen T, Niwa K, Hisatome I. et al. Increased serum uric acid over five years is a risk factor for developing fatty liver. Sci Rep 2018; 8 (01) 11735
- 38 Huang H, Huang B, Li Y. et al. Uric acid and risk of heart failure: a systematic review and meta-analysis. Eur J Heart Fail 2014; 16 (01) 15-24
- 39 Lu J, Sun M, Wu X. et al. Urate-lowering therapy alleviates atherosclerosis inflammatory response factors and neointimal lesions in a mouse model of induced carotid atherosclerosis. FEBS J 2019; 286 (07) 1346-1359
- 40 Mast AE. Tissue factor pathway inhibitor: multiple anticoagulant activities for a single protein. Arterioscler Thromb Vasc Biol 2016; 36 (01) 9-14
- 41 Cimmino G, Cirillo P. Tissue factor: newer concepts in thrombosis and its role beyond thrombosis and hemostasis. Cardiovasc Diagn Ther 2018; 8 (05) 581-593
- 42 Broze Jr GJ. Tissue factor pathway inhibitor and the current concept of blood coagulation. Blood Coagul Fibrinolysis 1995; 6 (1, Suppl 1): S7-S13
- 43 Abumiya T, Yamaguchi T, Terasaki T, Kokawa T, Kario K, Kato H. Decreased plasma tissue factor pathway inhibitor activity in ischemic stroke patients. Thromb Haemost 1995; 74 (04) 1050-1054
- 44 Dahm A, Van Hylckama Vlieg A, Bendz B, Rosendaal F, Bertina RM, Sandset PM. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101 (11) 4387-4392
- 45 Morange PE, Blankenberg S, Alessi MC. et al; Atherogene Investigators. Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 2007; 5 (03) 475-482
- 46 Wilson SH, Best PJ, Edwards WD. et al. Nuclear factor-kappaB immunoreactivity is present in human coronary plaque and enhanced in patients with unstable angina pectoris. Atherosclerosis 2002; 160 (01) 147-153
- 47 Petit L, Lesnik P, Dachet C. et al. The promoter of human tissue factor pathway inhibitor gene: identification of potential regulatory elements. Thromb Res 1999; 95 (05) 255-262
- 48 Amini Nekoo A, Iles D. Analysis of a T-287C polymorphism in the tissue factor pathway inhibitor gene and identification of a repressor element in the promoter. Thromb Res 2008; 121 (06) 813-819
- 49 Carver BJ, Plosa EJ, Stinnett AM, Blackwell TS, Prince LS. Interactions between NF-κB and SP3 connect inflammatory signaling with reduced FGF-10 expression. J Biol Chem 2013; 288 (21) 15318-15325
- 50 Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 2016; 16 (07) 407-420