SpringerLink
Log in

Role of Soluble Urokinase-Type Plasminogen Activator Receptor in Cardiovascular Disease

  • Cardiac Biomarkers (AA Quyyumi, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Chronic inflammation is a major contributor to cardiovascular disease (CVD) risk. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived glycoprotein that is strongly associated with atherosclerotic disease. This review summarizes evidence on suPAR’s role in CVD pathogenesis and its potential as a prognostic indicator and therapeutic target.

Recent Findings

Clinical, genetic, and experimental evidence supports suPAR’s role as a pathogenic factor in atherosclerosis. suPAR promotes atherosclerosis through modulation of monocyte activation and function. Clinically, elevated suPAR levels are linked to increased cardiovascular risk across diverse populations. Ongoing clinical trials are evaluating therapies targeting suPAR signaling.

Summary

Current evidence positions suPAR as a regulator of myeloid cell function that contributes to vascular inflammation and subsequent cardiovascular events. Additional research is needed to determine whether suPAR measurement can improve CVD risk prediction and enable personalized management. Overall, suPAR is a promising immune-derived biomarker and target for reducing inflammation and cardiovascular risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as:  •  Of importance  ••  Of major importance

  1. Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023;148(9):e9–119. https://doi.org/10.1161/CIR.0000000000001168.

    Article  PubMed  Google Scholar 

  2. Ridker PM. How common is residual inflammatory risk? Circ Res. 2017;120(4):617–9. https://doi.org/10.1161/CIRCRESAHA.116.310527.

    Article  CAS  PubMed  Google Scholar 

  3. Ridker PM, Bhatt DL, Pradhan AD, Glynn RJ, MacFadyen JG, Nissen SE, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet. 2023;401(10384):1293–301. https://doi.org/10.1016/S0140-6736(23)00215-5.

    Article  CAS  PubMed  Google Scholar 

  4. Ridker PM, Tuttle KR, Perkovic V, Libby P, MacFadyen JG. Inflammation drives residual risk in chronic kidney disease: a CANTOS substudy. Eur Heart J. 2022;43(46):4832–44. https://doi.org/10.1093/eurheartj/ehac444.

    Article  CAS  PubMed  Google Scholar 

  5. Del Buono MG, Montone RA, Iannaccone G, Rinaldi R, La Vecchia G, Camilli M, et al. Redefining residual inflammatory risk after acute coronary syndrome. Future Cardiol. 2022;18(2):115–23. https://doi.org/10.2217/fca-2021-0032.

    Article  CAS  PubMed  Google Scholar 

  6. Deftereos SG, Beerkens FJ, Shah B, Giannopoulos G, Vrachatis DA, Giotaki SG, et al. Colchicine in cardiovascular disease: in-depth review. Circulation. 2022;145(1):61–78. https://doi.org/10.1161/CIRCULATIONAHA.121.056171.

    Article  CAS  PubMed  Google Scholar 

  7. •• Hindy G, Tyrrell DJ, Vasbinder A, Wei C, Presswalla F, Wang H, et al. Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis. J Clin Invest. 2022;132(24). https://doi.org/10.1172/JCI158788. Findings from this study provide clinical, genetic and experimental evidence of a causal role of suPAR in atherosclerosis. High suPAR levels pomote atheroscleorsis through myeloid cell activation and are strongly associated with adverse cardiovascular outcomes.

  8. Rasmussen LJH, Petersen JEV, Eugen-Olsen J. Soluble urokinase plasminogen activator receptor (suPAR) as a biomarker of systemic chronic inflammation. Front Immunol. 2021;12:780641. https://doi.org/10.3389/fimmu.2021.780641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. https://www.waldenbiosciences.com/walden-biosciences-announces-first-subject-dosed-in-first-in-humans-phase-1-clinical-trial-of-wal0921-in-development-for-treatment-of-chronic-kidney-diseases/ Accessed.

  10. Olsen MB, Gregersen I, Sandanger O, Yang K, Sokolova M, Halvorsen BE, et al. Targeting the inflammasome in cardiovascular disease. JACC Basic Transl Sci. 2022;7(1):84–98. https://doi.org/10.1016/j.jacbts.2021.08.006.

    Article  PubMed  Google Scholar 

  11. Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res. 2019;124(2):315–27. https://doi.org/10.1161/CIRCRESAHA.118.313591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schnitzler JG, Hoogeveen RM, Ali L, Prange KHM, Waissi F, van Weeghel M, et al. Atherogenic lipoprotein(a) increases vascular glycolysis, thereby facilitating inflammation and leukocyte extravasation. Circ Res. 2020;126(10):1346–59. https://doi.org/10.1161/CIRCRESAHA.119.316206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jaipersad AS, Lip GY, Silverman S, Shantsila E. The role of monocytes in angiogenesis and atherosclerosis. J Am Coll Cardiol. 2014;63(1):1–11. https://doi.org/10.1016/j.jacc.2013.09.019.

    Article  CAS  PubMed  Google Scholar 

  14. Tabas I, Bornfeldt KE. Macrophage phenotype and function in different stages of atherosclerosis. Circ Res. 2016;118(4):653–67. https://doi.org/10.1161/CIRCRESAHA.115.306256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Roy P, Orecchioni M, Ley K. How the immune system shapes atherosclerosis: roles of innate and adaptive immunity. Nat Rev Immunol. 2022;22(4):251–65. https://doi.org/10.1038/s41577-021-00584-1.

    Article  CAS  PubMed  Google Scholar 

  16. Yu S, Sui Y, Wang J, Li Y, Li H, Cao Y, et al. Crystal structure and cellular functions of uPAR dimer. Nat Commun. 2022;13(1):1665. https://doi.org/10.1038/s41467-022-29344-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. PLAUR plasminogen activator, urokinase receptor [Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene/5329 Accessed.

  18. Alfano D, Franco P, Stoppelli MP. Modulation of cellular function by the urokinase receptor signalling: a mechanistic view. Front Cell Dev Biol. 2022;10:818616. https://doi.org/10.3389/fcell.2022.818616.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hahm E, Wei C, Fernandez I, Li J, Tardi NJ, Tracy M, et al. Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med. 2017;23(1):100–6. https://doi.org/10.1038/nm.4242.

    Article  CAS  PubMed  Google Scholar 

  20. Wang Y, Dang J, Wang H, Allgayer H, Murrell GA, Boyd D. Identification of a novel nuclear factor-kappaB sequence involved in expression of urokinase-type plasminogen activator receptor. Eur J Biochem. 2000;267(11):3248–54. https://doi.org/10.1046/j.1432-1327.2000.01350.x.

    Article  CAS  PubMed  Google Scholar 

  21. Montuori N, Ragno P. Multiple activities of a multifaceted receptor: roles of cleaved and soluble uPAR. Front Biosci (Landmark Ed). 2009;14(7):2494–503. https://doi.org/10.2741/3392.

    Article  CAS  PubMed  Google Scholar 

  22. Thuno M, Macho B, Eugen-Olsen J. suPAR: the molecular crystal ball. Dis Markers. 2009;27(3):157–72. https://doi.org/10.3233/DMA-2009-0657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vasbinder A, Raffield LM, Gao Y, Engstrom G, Quyyumi AA, Reiner AP, et al. Assay-related differences in SuPAR levels: implications for measurement and data interpretation. J Nephrol. 2023;36(1):157–9. https://doi.org/10.1007/s40620-022-01344-7.

    Article  CAS  PubMed  Google Scholar 

  24. Hayek SS, Koh KH, Grams ME, Wei C, Ko YA, Li J, et al. A tripartite complex of suPAR, APOL1 risk variants and alpha(v)beta(3) integrin on podocytes mediates chronic kidney disease. Nat Med. 2017;23(8):945–53. https://doi.org/10.1038/nm.4362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sudhini YR, Wei C, Reiser J. suPAR: an inflammatory mediator for kidneys. Kidney Dis (Basel). 2022;8(4):265–74. https://doi.org/10.1159/000524965.

    Article  PubMed  Google Scholar 

  26. Olson NC, Raffield LM, Moxley AH, Miller-Fleming TW, Auer PL, Franceschini N, et al. Soluble urokinase plasminogen activator receptor: genetic variation and cardiovascular disease risk in black adults. Circ Genom Precis Med. 2021;14(6):e003421. https://doi.org/10.1161/CIRCGEN.121.003421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nusshag C, Wei C, Hahm E, Hayek SS, Li J, Samelko B, et al. suPAR links a dysregulated immune response to tissue inflammation and sepsis-induced acute kidney injury. JCI Insight. 2023;8(7). https://doi.org/10.1172/jci.insight.165740.

  28. Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol. 2010;11(1):23–36. https://doi.org/10.1038/nrm2821.

    Article  CAS  PubMed  Google Scholar 

  29. Pliyev BK, Antonova OA, Menshikov M. Participation of the urokinase-type plasminogen activator receptor (uPAR) in neutrophil transendothelial migration. Mol Immunol. 2011;48(9–10):1168–77. https://doi.org/10.1016/j.molimm.2011.02.011.

    Article  CAS  PubMed  Google Scholar 

  30. Rosetti F, Mayadas TN. The many faces of Mac-1 in autoimmune disease. Immunol Rev. 2016;269(1):175–93. https://doi.org/10.1111/imr.12373.

    Article  CAS  PubMed  Google Scholar 

  31. Alfano M, Cinque P, Giusti G, Proietti S, Nebuloni M, Danese S, et al. Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes. Sci Rep. 2015;5:13647. https://doi.org/10.1038/srep13647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wei C, Li J, Adair BD, Zhu K, Cai J, Merchant M, et al. uPAR isoform 2 forms a dimer and induces severe kidney disease in mice. J Clin Invest. 2019;129(5):1946–59. https://doi.org/10.1172/JCI124793.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Chen W, ** WQ, Chen LF, Williams T, Zhu WL, Fang Q. Urokinase receptor surface expression regulates monocyte migration and is associated with accelerated atherosclerosis. Int J Cardiol. 2012;161(2):103–10. https://doi.org/10.1016/j.ijcard.2011.12.094.

    Article  PubMed  Google Scholar 

  34. Gu JM, Johns A, Morser J, Dole WP, Greaves DR, Deng GG. Urokinase plasminogen activator receptor promotes macrophage infiltration into the vascular wall of ApoE deficient mice. J Cell Physiol. 2005;204(1):73–82. https://doi.org/10.1002/jcp.20262.

    Article  CAS  PubMed  Google Scholar 

  35. Dai C, Lin Y. Comprehensive analysis of the diagnostic and therapeutic value of the hypoxia-related gene PLAUR in the progression of atherosclerosis. Sci Rep. 2023;13(1):8533. https://doi.org/10.1038/s41598-023-35548-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lyngbaek S, Marott JL, Sehestedt T, Hansen TW, Olsen MH, Andersen O, et al. Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score. Int J Cardiol. 2013;167(6):2904–11. https://doi.org/10.1016/j.ijcard.2012.07.018.

    Article  PubMed  Google Scholar 

  37. Mehta A, Desai SR, Ko YA, Liu C, Dhindsa DS, Nayak A, et al. Sex differences in circulating soluble urokinase-type plasminogen activator receptor (suPAR) levels and adverse outcomes in coronary artery disease. J Am Heart Assoc. 2020;9(5):e015457. https://doi.org/10.1161/JAHA.119.015457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Haupt TH, Kallemose T, Ladelund S, Rasmussen LJ, Thorball CW, Andersen O, et al. Risk factors associated with serum levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor in a general population. Biomark Insights. 2014;9:91–100. https://doi.org/10.4137/BMI.S19876.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Gozdzik W, Adamik B, Gozdzik A, Rachwalik M, Kustrzycki W, Kubler A. Unchanged plasma levels of the soluble urokinase plasminogen activator receptor in elective coronary artery bypass graft surgery patients and cardiopulmonary bypass use. PLoS ONE. 2014;9(6):e98923. https://doi.org/10.1371/journal.pone.0098923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lyngbaek S, Marott JL, Moller DV, Christiansen M, Iversen KK, Clemmensen PM, et al. Usefulness of soluble urokinase plasminogen activator receptor to predict repeat myocardial infarction and mortality in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous intervention. Am J Cardiol. 2012;110(12):1756–63. https://doi.org/10.1016/j.amjcard.2012.08.008.

    Article  CAS  PubMed  Google Scholar 

  41. Vasbinder A, Anderson E, Shadid H, Berlin H, Pan M, Azam TU, et al. Inflammation, hyperglycemia, and adverse outcomes in individuals with diabetes mellitus hospitalized for COVID-19. Diabetes Care. 2022;45(3):692–700. https://doi.org/10.2337/dc21-2102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Botha S, Fourie CM, Schutte R, Kruger A, Schutte AE. Associations of suPAR with lifestyle and cardiometabolic risk factors. Eur J Clin Invest. 2014;44(7):619–26. https://doi.org/10.1111/eci.12278.

    Article  CAS  PubMed  Google Scholar 

  43. Haupt TH, Rasmussen LJH, Kallemose T, Ladelund S, Andersen O, Pisinger C, et al. Healthy lifestyles reduce suPAR and mortality in a Danish general population study. Immun Ageing. 2019;16:1. https://doi.org/10.1186/s12979-018-0141-8.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hayek SS, Sever S, Ko YA, Trachtman H, Awad M, Wadhwani S, et al. Soluble urokinase receptor and chronic kidney disease. N Engl J Med. 2015;373(20):1916–25. https://doi.org/10.1056/NEJMoa1506362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Eugen-Olsen J, Ladelund S, Sorensen LT. Plasma suPAR is lowered by smoking cessation: a randomized controlled study. Eur J Clin Invest. 2016;46(4):305–11. https://doi.org/10.1111/eci.12593.

    Article  CAS  PubMed  Google Scholar 

  46. Wei C, Datta PK, Siegerist F, Li J, Yashwanth S, Koh KH, et al. SuPAR mediates viral response proteinuria by rapidly changing podocyte function. Nat Commun. 2023;14(1):4414. https://doi.org/10.1038/s41467-023-40165-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Huttunen R, Syrjanen J, Vuento R, Hurme M, Huhtala H, Laine J, et al. Plasma level of soluble urokinase-type plasminogen activator receptor as a predictor of disease severity and case fatality in patients with bacteraemia: a prospective cohort study. J Intern Med. 2011;270(1):32–40. https://doi.org/10.1111/j.1365-2796.2011.02363.x.

    Article  CAS  PubMed  Google Scholar 

  48. Sidenius N, Sier CF, Ullum H, Pedersen BK, Lepri AC, Blasi F, et al. Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection. Blood. 2000;96(13):4091–5.

    Article  CAS  PubMed  Google Scholar 

  49. Sorensen MH, Gerke O, Eugen-Olsen J, Munkholm H, Lambrechtsen J, Sand NP, et al. Soluble urokinase plasminogen activator receptor is in contrast to high-sensitive C-reactive-protein associated with coronary artery calcifications in healthy middle-aged subjects. Atherosclerosis. 2014;237(1):60–6. https://doi.org/10.1016/j.atherosclerosis.2014.08.035.

    Article  CAS  PubMed  Google Scholar 

  50. Hayek SS, Divers J, Raad M, Xu J, Bowden DW, Tracy M, et al. Predicting mortality in African Americans with type 2 diabetes mellitus: soluble urokinase plasminogen activator receptor, coronary artery calcium, and high-sensitivity C-reactive protein. J Am Heart Assoc. 2018;7(9). https://doi.org/10.1161/JAHA.117.008194.

  51. Guan J, Gong S, He Q, Wang X, Shen S, Wu X, et al. Soluble urokinase plasminogen activator receptor is associated with cardiovascular calcification in peritoneal dialysis patients. Int Urol Nephrol. 2023. https://doi.org/10.1007/s11255-023-03623-z.

    Article  PubMed  Google Scholar 

  52. Wu W, Cui Y, Hu J, Liao R, Li S, Mo L, et al. Soluble urokinase plasminogen activator receptor is associated with coronary artery calcification and cardiovascular disease in patients undergoing hemodialysis. Kidney Blood Press Res. 2018;43(3):664–72. https://doi.org/10.1159/000489623.

    Article  CAS  PubMed  Google Scholar 

  53. Eapen DJ, Manocha P, Ghasemzadeh N, Patel RS, Al Kassem H, Hammadah M, et al. Soluble urokinase plasminogen activator receptor level is an independent predictor of the presence and severity of coronary artery disease and of future adverse events. J Am Heart Assoc. 2014;3(5):e001118. https://doi.org/10.1161/JAHA.114.001118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Walter JE, Amrein MLF, Schafer I, Zimmermann T, Lopez-Ayala P, Boeddinghaus J, et al. Soluble urokinase plasminogen activator receptor and functionally relevant coronary artery disease: a prospective cohort study. Biomarkers. 2022;27(3):278–85. https://doi.org/10.1080/1354750X.2022.2038269.

    Article  CAS  PubMed  Google Scholar 

  55. Mekonnen G, Corban MT, Hung OY, Eshtehardi P, Eapen DJ, Al-Kassem H, et al. Plasma soluble urokinase-type plasminogen activator receptor level is independently associated with coronary microvascular function in patients with non-obstructive coronary artery disease. Atherosclerosis. 2015;239(1):55–60. https://doi.org/10.1016/j.atherosclerosis.2014.12.025.

    Article  CAS  PubMed  Google Scholar 

  56. Corban MT, Prasad A, Nesbitt L, Loeffler D, Herrmann J, Lerman LO, et al. Local production of soluble urokinase plasminogen activator receptor and plasminogen activator inhibitor-1 in the coronary circulation is associated with coronary endothelial dysfunction in humans. J Am Heart Assoc. 2018;7(15):e009881. https://doi.org/10.1161/JAHA.118.009881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lin WC, Wu TJ, Wang CH, Hsieh YJ, Hsu BG. Association between serum soluble urokinase-type plasminogen activator receptor level and arterial stiffness in chronic hemodialysis patients. J Pers Med. 2023;13(3). https://doi.org/10.3390/jpm13030470.

  58. Bocskei RM, Benczur B, Losonczy G, Illyes M, Cziraki A, Muller V, et al. Soluble urokinase-type plasminogen activator receptor and arterial stiffness in patients with COPD. Lung. 2019;197(2):189–97. https://doi.org/10.1007/s00408-019-00211-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schutte AE, Myburgh A, Olsen MH, Eugen-Olsen J, Schutte R. Exploring soluble urokinase plasminogen activator receptor and its relationship with arterial stiffness in a bi-ethnic population: the SAfrEIC-study. Thromb Res. 2012;130(2):273–7. https://doi.org/10.1016/j.thromres.2011.10.034.

    Article  CAS  PubMed  Google Scholar 

  60. Pawlak K, Mysliwiec M, Pawlak D. The urokinase-type plasminogen activator/its soluble receptor system is independently related to carotid atherosclerosis and associated with CC-chemokines in uraemic patients. Thromb Res. 2008;122(3):328–35. https://doi.org/10.1016/j.thromres.2007.10.017.

    Article  CAS  PubMed  Google Scholar 

  61. Persson M, Ostling G, Smith G, Hamrefors V, Melander O, Hedblad B, et al. Soluble urokinase plasminogen activator receptor: a risk factor for carotid plaque, stroke, and coronary artery disease. Stroke. 2014;45(1):18–23. https://doi.org/10.1161/STROKEAHA.113.003305.

    Article  CAS  PubMed  Google Scholar 

  62. Sehestedt T, Lyngbaek S, Eugen-Olsen J, Jeppesen J, Andersen O, Hansen TW, et al. Soluble urokinase plasminogen activator receptor is associated with subclinical organ damage and cardiovascular events. Atherosclerosis. 2011;216(1):237–43. https://doi.org/10.1016/j.atherosclerosis.2011.01.049.

    Article  CAS  PubMed  Google Scholar 

  63. Samman Tahhan A, Hayek SS, Sandesara P, Hajjari J, Hammadah M, O’Neal WT, et al. Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes. Atherosclerosis. 2017;264:108–14. https://doi.org/10.1016/j.atherosclerosis.2017.06.019.

    Article  CAS  PubMed  Google Scholar 

  64. • Hayek SS, Tahhan AS, Ko YA, Alkhoder A, Zheng S, Bhimani R, et al. Soluble urokinase plasminogen activator receptor levels and outcomes in patients with heart failure. J Card Fail. 2023;29(2):158–67. https://doi.org/10.1016/j.cardfail.2022.08.010. Findings from this study suggest that suPAR is strongly predictive of cardiovascular outcomes (death, CV death, hospitalization for heart failure) in patients with heart failure.

    Article  PubMed  Google Scholar 

  65. Wettersten N, Katz R, Greenberg JH, Gutierrez OM, Lima JAC, Sarnak MJ, et al. Association of kidney tubule biomarkers with cardiac structure and function in the multiethnic study of atherosclerosis. Am J Cardiol. 2023;196:11–8. https://doi.org/10.1016/j.amjcard.2023.02.031.

    Article  CAS  PubMed  Google Scholar 

  66. Koller L, Stojkovic S, Richter B, Sulzgruber P, Potolidis C, Liebhart F, et al. Soluble urokinase-type plasminogen activator receptor improves risk prediction in patients with chronic heart failure. JACC Heart Fail. 2017;5(4):268–77. https://doi.org/10.1016/j.jchf.2016.12.008.

    Article  PubMed  Google Scholar 

  67. Fujita SI, Tanaka S, Maeda D, Morita H, Fujisaka T, Takeda Y, et al. Serum soluble urokinase-type plasminogen activator receptor is associated with low left ventricular ejection fraction and elevated plasma brain-type natriuretic peptide level. PLoS ONE. 2017;12(1):e0170546. https://doi.org/10.1371/journal.pone.0170546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wlazel RN, Guligowska A, Chrzastek Z, Kostka T, Jegier A, Szadkowska I. Soluble urokinase-type plasminogen activator receptor (suPAR) is a biomarker associated with left ventricular hypertrophy in the elderly, specifically in women. J Clin Med. 2023;12(9). https://doi.org/10.3390/jcm12093290.

  69. Eugen-Olsen J, Andersen O, Linneberg A, Ladelund S, Hansen TW, Langkilde A, et al. Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med. 2010;268(3):296–308. https://doi.org/10.1111/j.1365-2796.2010.02252.x.

    Article  CAS  PubMed  Google Scholar 

  70. Persson M, Engstrom G, Bjorkbacka H, Hedblad B. Soluble urokinase plasminogen activator receptor in plasma is associated with incidence of CVD. Results from the Malmo Diet and Cancer Study. Atherosclerosis. 2012;220(2):502–5. https://doi.org/10.1016/j.atherosclerosis.2011.10.039.

  71. Ghasemzedah N, Hayek SS, Ko YA, Eapen DJ, Patel RS, Manocha P, et al. Pathway-specific aggregate biomarker risk score is associated with burden of coronary artery disease and predicts near-term risk of myocardial infarction and death. Circ Cardiovasc Qual Outcomes. 2017;10(3). https://doi.org/10.1161/CIRCOUTCOMES.115.001493.

  72. Al-Badri A, Tahhan AS, Sabbak N, Alkhoder A, Liu C, Ko YA, et al. Soluble urokinase-type plasminogen activator receptor and high-sensitivity troponin levels predict outcomes in nonobstructive coronary artery disease. J Am Heart Assoc. 2020;9(8):e015515. https://doi.org/10.1161/JAHA.119.015515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Claudia Sommerer SM-K, Jennifer Nadal, Ulla T. Schultheiss, Nele Friedrich, Matthias Nauck, Matthias Schmid, Christian Nußhag, Jochen Reiser, Kai-Uwe Eckardt, Martin Zeier, Salim S. Hayek. Prospective cohort study of soluble urokinase plasminogen activation receptor and cardiovascular events in patients with CKD. Kidney Int Rep. 2023. https://doi.org/10.1016/j.ekir.2023.08.038.

  74. Lyngbæk S, Marott JL, Sehestedt T, Hansen TW, Olsen MH, Andersen O, et al. Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score. Int J Cardiol. 2013;167(6):2904–11. https://doi.org/10.1016/j.ijcard.2012.07.018.

    Article  PubMed  Google Scholar 

  75. Borne Y, Persson M, Melander O, Smith JG, Engstrom G. Increased plasma level of soluble urokinase plasminogen activator receptor is associated with incidence of heart failure but not atrial fibrillation. Eur J Heart Fail. 2014;16(4):377–83. https://doi.org/10.1002/ejhf.49.

    Article  CAS  PubMed  Google Scholar 

  76. Peiro OM, Cediel G, Bonet G, Rojas S, Quintern V, Carrasquer A, et al. Soluble urokinase plasminogen activator receptor as a long-term prognostic biomarker in acute coronary syndromes. Biomarkers. 2020;25(5):402–9. https://doi.org/10.1080/1354750X.2020.1778090.

    Article  CAS  PubMed  Google Scholar 

  77. Mohebi R, Murphy S, Jackson L, McCarthy C, Abboud A, Murtagh G, et al. Biomarker prognostication across universal definition of heart failure stages. ESC Heart Fail. 2022;9(6):3876–87. https://doi.org/10.1002/ehf2.14071.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Nikorowitsch J, Borchardt T, Appelbaum S, Ojeda F, Lackner KJ, Schnabel RB, et al. Cardio-renal biomarker soluble urokinase-type plasminogen activator receptor is associated with cardiovascular death and myocardial infarction in patients with coronary artery disease independent of troponin, C-reactive protein, and renal function. J Am Heart Assoc. 2020;9(8):e015452. https://doi.org/10.1161/JAHA.119.015452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hodges G, Lyngbaek S, Selmer C, Ahlehoff O, Theilade S, Sehestedt TB, et al. SuPAR is associated with death and adverse cardiovascular outcomes in patients with suspected coronary artery disease. Scand Cardiovasc J. 2020;54(6):339–45. https://doi.org/10.1080/14017431.2020.1762917.

    Article  CAS  PubMed  Google Scholar 

  80. Westin O, Rasmussen LJH, Andersen O, Buch E, Olsen JE, Friberg J. Soluble urokinase plasminogen activator receptor (suPAR) as a predictor of incident atrial fibrillation. J Atr Fibrillation. 2018;10(6):1801. https://doi.org/10.4022/jafib.1801.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Lazarevic M, Golubovic M, Milic D, Stanojevic D, Kostic T, Dordevic M, et al. Preoperative levels of the soluble urokinase-type plasminogen activator receptor as predictor for new episodes of atrial fibrillation after vascular surgery. Vasc Endovascular Surg. 2021;55(5):461–6. https://doi.org/10.1177/1538574421995321.

    Article  PubMed  Google Scholar 

  82. Jankowski J, Floege J, Fliser D, Bohm M, Marx N. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation. 2021;143(11):1157–72. https://doi.org/10.1161/CIRCULATIONAHA.120.050686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Drechsler C, Hayek SS, Wei C, Sever S, Genser B, Krane V, et al. Soluble urokinase plasminogen activator receptor and outcomes in patients with diabetes on hemodialysis. Clin J Am Soc Nephrol. 2017;12(8):1265–73. https://doi.org/10.2215/CJN.10881016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Meijers B, Poesen R, Claes K, Dietrich R, Bammens B, Sprangers B, et al. Soluble urokinase receptor is a biomarker of cardiovascular disease in chronic kidney disease. Kidney Int. 2015;87(1):210–6. https://doi.org/10.1038/ki.2014.197.

    Article  CAS  PubMed  Google Scholar 

  85. Takahashi J, Yamamoto M, Yasukawa H, Nohara S, Nagata T, Shimozono K, et al. Interleukin-22 directly activates myocardial STAT3 (signal transducer and activator of transcription-3) signaling pathway and prevents myocardial ischemia reperfusion injury. J Am Heart Assoc. 2020;9(8):e014814. https://doi.org/10.1161/JAHA.119.014814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Saleem MA. What is the role of soluble urokinase-type plasminogen activator in renal disease? Nephron. 2018;139(4):334–41. https://doi.org/10.1159/000490118.

    Article  CAS  PubMed  Google Scholar 

  87. Engstrom G, Zoller B, Svensson PJ, Melander O, Persson M. Soluble urokinase plasminogen activator receptor and incidence of venous thromboembolism. Thromb Haemost. 2016;115(3):657–62. https://doi.org/10.1160/TH15-06-0511.

    Article  PubMed  Google Scholar 

  88. Sommerer C, Zeier M, Morath C, Reiser J, Scharnagl H, Stojakovic T, et al. Soluble urokinase plasminogen activation receptor and long-term outcomes in persons undergoing coronary angiography. Sci Rep. 2019;9(1):475. https://doi.org/10.1038/s41598-018-36960-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Santeri S, Peter AA, Kristiina N, Jesper EO, Harri H. suPAR cut-offs for stratification of low, medium, and high-risk acute medical patients in the emergency department. BMC Emerg Med. 2021;21(1):149. https://doi.org/10.1186/s12873-021-00544-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Altintas I, Eugen-Olsen J, Seppala S, Tingleff J, Stauning MA, El Caidi NO, et al. suPAR cut-offs for risk stratification in patients with symptoms of COVID-19. Biomark Insights. 2021;16:11772719211034684. https://doi.org/10.1177/11772719211034685.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Schultz M, Rasmussen LJH, Andersen MH, Stefansson JS, Falkentoft AC, Alstrup M, et al. Use of the prognostic biomarker suPAR in the emergency department improves risk stratification but has no effect on mortality: a cluster-randomized clinical trial (TRIAGE III). Scand J Trauma Resusc Emerg Med. 2018;26(1):69. https://doi.org/10.1186/s13049-018-0539-5.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

SSH is supported by NHLBI R01HL153384, NIDDK R01DK128012, and the Gilead Sciences Research Scholar Program.

Author information

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, 1500 E Medical Center Dr, CVC #2709, Ann Arbor, 48109, MI, USA

    Anis Ismail & Salim S. Hayek

Authors
  1. Anis Ismail
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Salim S. Hayek
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AI wrote the first draft. SSH reviewed and edited the manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to Salim S. Hayek.

Ethics declarations

Conflict of Interest

Anis Ismail has no conflicts of interest. Salim S. Hayek reports personal fees from Walden Biosciences and Siemens, outside the submitted work. In addition, Dr. Hayek has patents pending on “Use of soluble urokinase plasminogen activator receptor levels in the management of patients with cardiovascular disease” and “Methods to target the soluble urokinase plasminogen activator receptor pathway for the prevention and treatment of atherosclerosis.”

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ismail, A., Hayek, S.S. Role of Soluble Urokinase-Type Plasminogen Activator Receptor in Cardiovascular Disease. Curr Cardiol Rep 25, 1797–1810 (2023). https://doi.org/10.1007/s11886-023-01991-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11886-023-01991-7

Keywords

Search

Navigation