Hyperuricemia and NLRP3 inflammasome activity in the concept of metabolic syndrome and cardiovascular diseases

From the modern point of view, hyperuricemia should be considered as a trigger of inflammatory activity leading to specific joint and renal lesions, as well as to diseases associated with atherosclerosis. HU is also recognized as one of the components of metabolic syndrome, which is characterized by involvement of liver parenchyma with the development of fatty disease, insulin resistance, which promotes glycemia, dyslipidemia, inflammatory activity of the vascular wall associated with endothelial dysfunction. Recently, a universal mechanism of inflammation has been established involving the NLRP3 inflammasome, which generates a key mediator of gout attacks, IL-1β, responsible for the local inflammatory response in the synovial membrane and periarticular tissues involving macrophages and neutrophils. This cytokine is also involved in the inflammatory process characteristic of atherosclerosis, stimulating the release of other cytokines (IL-6 and IL-18), production of endothelin 1 and adhesion molecules, causing migration of leukocytes into the intima, initiating and destabilizing the atherosclerotic plaque. NLRP3 inflammasome activation is carried out by uric acid and cholesterol crystals exclusively after priming by lipopolysaccharides, peroxidation products and other damage factors associated with aging and comorbid conditions typical of gout and cardiovascular diseases. In addition, NLRP3 inflammasome activity is genetically determined with respect to these conditions. This paper provides evidence that targeting factors associated with comorbidity can not only reduce the frequency of gout attacks, but also reduce cardiovascular outcomes. Blocking inflammasome activity is considered as a new universal therapeutic target for rheumatology and cardiology, especially in high cardiovascular risk conditions, which include metabolic syndrome associated with hyperuricemia.

NLRP3 inflammasome, hyperuricemia, metabolic syndrome, atherogenesis

1. Shal’nova S. A., Deyev A.D., Artamonova G.V. i soavt. Giperurikemiya i yeye korrelyaty v Rossiyskoy populyatsii (rezul’taty epidemiologicheskogo issledovaniya ESSE RF). [Hyperuricemia and its correlates in the Russian population (results of an epidemiological study by ESSE RF)] Ratsional’naya farmakoterapiya v kardiologii. 2014; 10 (2): 153-159. doi: 10.20996/1819-6446-2014-10-2-153-159.@@ Шальнова С.А., Деев А.Д., Артамонова Г.В. и соавт. Гиперурикемия и ее корреляты в Российской популяции (результаты эпидемиологического исследования ЭССЕ РФ). Рациональная фармакотерапия в кардиологии. 2014; 10 (2): 153-159.

2. Zuo T., Liu X., Jiang L. et al. Hyperuricemia and coronary heart disease mortality: a meta-analysis of prospective cohort studies. BMC Cardiovasc Disord 16, 207 (2016). doi: 1186/s12872-016-0379-z.

3. Saito Y., Tanaka A., Node K., Kobayashi Y. Uric acid and cardiovascular disease: A clinical review. J Cardiol. 2021 Jul;78(1):51-57. doi: 10.1016/j.jjcc.2020.12.013.

4. Li X., Meng X., Timofeeva M. et al. Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies. BMJ. 2017 Jun 7;357: j2376. doi: 10.1136/bmj.j2376.

5. Efstathiadou A., Gill D., McGrane F. et al. Genetically Determined Uric Acid and the Risk of Cardiovascular and Neurovascular Diseases: A Mendelian Randomization Study of Outcomes Investigated in Randomized Trials. J Am Heart Assoc. 2019 Sep 3;8(17): e012738. doi: 10.1161/JAHA.119.012738.

6. Wang K., Shi X., Zhu Z. et al. Mendelian randomization analysis of 37 clinical factors and coronary artery disease in East Asian and European populations. Genome Med. 2022;14:63. doi: 10.1186/s13073-022-01067-1

7. Glantzounis G.K., Tsimoyiannis E.C., Kappas A.M., Galaris D.A. Uric acid and oxidative stress. Curr Pharm Des. (2005) 11:4145-51. doi: 10.2174/138161205774913255.

8. Lai J.H., Luo S.F., Hung L.F. et al. Physiological concentrations of soluble uric acid are chondroprotective and anti-inflammatory. Sci Rep 7, 2359 (2017). doi: 10.1038/s41598-017-02640-0

9. Moon K.W. Mortality rate of gout patients has been increased in Korea Annals of the Rheumatic Diseases 82(Suppl 1):523.2-524. doi: 10.1136/annrheumdis-2023- eular.4032.

10. Hansildaar R., Vedder D., Baniaamam M. et al. Cardiovascular risk in inflammatory arthritis: rheumatoid arthritis and gout. Lancet Rheumatol. 2021 Jan;3(1): e58-e70. doi: 10.1016/S2665-9913(20)30221-6.

11. Kang H.S., Lee N.E., Yoo D.M. et al. An elevated likelihood of stroke, ischemic heart disease, or heart failure in individuals with gout: a longitudinal follow-up study utilizing the National Health Information database in Korea. Front Endocrinol (Lausanne). 2023;23;14:1195888. doi: 10.3389/fendo.2023.1195888.

12. Kuo C.F, Grainge M.J., Zhang W., Doherty M. Global epidemiology of gout: prevalence, incidence and risk factors. Nat Rev Rheumatol. 2015 Nov;11(11):649-62. doi: 10.1038/nrrheum.2015.91.

13. Hansildaar R., Vedder D., Baniaamam M. et al. Cardiovascular risk in inflammatory arthritis: rheumatoid arthritis and gout. Lancet Rheumatol. 2021 Jan;3(1): e58-e70. doi: 10.1016/S2665-9913(20)30221-6.

14. Klauser A.S., Halpern E.J., Strobl S. et al. Dual-energy computed tomography detection of cardiovascular monosodium urate deposits in patients with gout. JAMA Cardiol. 2019;4:1019-1028. doi: 10.1001/jamacardio.2019.3201.

15. Barazani S.H., Chi W.W., Pyzik R. et al. Quantification of uric acid in vasculature of patients with gout using dual-energy computed tomography. World J Radiol. 2020;12:184-194. doi: 10.4329/wjr.v12.i8.184.

16. Strandberg T.E., Kovanen P.T. Coronary artery disease: ‘gout’ in the artery? European Heart Journal. 2021;42:2761-2764. VIEWPOINT. doi: 10.1093/eurheartj/ehab276.

17. Lee J.S., Kwon O.C., Oh J.S. et al. Clinical features and recurrent attack in gout patients according to serum urate levels during an acute attack. Korean J Intern Med. 2020 Jan;35(1):240-248. doi: 10.3904/kjim.2018.205.

18. Chen J., Wu M., Yang J. et al. The Immunological Basis in the Pathogenesis of Gout. Iran J Immunol. 2017 Jun;14(2):90-98.

19. Peng T.C., Wang C.C., Kao T.W. et al. Relationship between hyperuricemia and lipid profiles in US adults. Biomed Res Int. 2015;2015:127596. doi: 10.1155/2015/127596.

20. Baldwin W., McRae S., Marek G. et al. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes. 2011;60(4):1258-1269. doi: 10.2337/db10-0916.

21. Fang Y.J., Wu T.Y., Lin C.L. et al. Effects of Urate-Lowering Therapy on Risk of Hyperlipidemia in Gout by a Population-Based Cohort Study and on In Vitro Hepatic Lipogenesis-Related Gene Expression. Mediators Inflamm. 2020 Nov 14;2020:8890300. doi: 10.1155/2020/8890300.

22. Wu K.K., Cheung S.W., Cheng K.K. NLRP3 Inflammasome Activation in Adipose Tissues and Its Implications on Metabolic Diseases.Int J Mol Sci. 2020 Jun 11;21(11):4184. doi: 10.3390/ijms21114184.

23. Bando S., Fukuda D., Soeki T. et al. Expression of NLRP3 in subcutaneous adipose tissue is associated with coronary atherosclerosis. Atherosclerosis. 2015 Oct;242(2):407-14. doi: 10.1016/j.atherosclerosis.2015.07.043.

24. Koenen T.B., Stienstra R., van Tits L.J. et al. Hyperglycemia activates caspase-1 and TXNIP-mediated IL-1beta transcription in human adipose tissue. Diabetes. 2011 Feb;60(2):517-24. doi: 10.2337/db10-0266.

25. Vandanmagsar B., Youm Y.H., Ravussin A. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011 Feb;17(2):179-88. doi: 10.1038/nm.2279.

26. Mylona E.E., Mouktaroudi M., Crisan T.O. et al. Enhanced interleukin-1β production of PBMCs from patients with gout after stimulation with Toll-like receptor-2 ligands and urate crystals. Arthritis Res Ther. 2012 Jul 4;14(4): R158. doi: 10.1186/ar3898.

27. Tong Y., Wang Z., Cai L. et al. NLRP3 Inflammasome and Its Central Role in the Cardiovascular Diseases. Oxid Med Cell Longev. 14;2020:4293206. doi: 10.1155/2020/4293206.

28. Clavijo-Cornejo D., López-Reyes A., Cruz-Arenas E. et al. Inflammasome genes polymorphisms and susceptibility to gout. Is there a link? Rev Invest Clin. 2022 May 2;74(3):147-155. doi: 10.24875/RIC.21000603.

29. Zhang Q.B., Qing Y.F., He Y.L. al. Association of NLRP3 polymorphisms with susceptibility to primary gouty arthritis in a Chinese Han population. Clin Rheumatol. 2018 Jan;37(1):235-244. doi: 10.1007/s10067-017-3900-6.

30. Liu Y.R., Wang J.Q., Li J. Role of NLRP3 in the pathogenesis and treatment of gout arthritis. Front Immunol. 2023 Mar 27;14:1137822. doi: 10.3389/fimmu.2023.1137822.

31. Schlesinger N., Pillinger M.H., Simon L.S. et al.Interleukin-1β inhibitors for the management of acute gout flares: a systematic literature review. Arthritis Res Ther. 2023 Jul 25;25(1):128. doi: 10.1186/s13075-023-03098-4.

32. Panevin T.S., Eliseev M.S., Nasonov E.L. Urate-lowering drugs in the treatment of gout: The unknown about the known. Rheumatology Science and Practice. 2021;59(6):727-737. (In Russ.) doi: 10.47360/1995-4484-2021-727-737.@@ Паневин Т.С., Елисеев М.С., Насонов Е.Л. Уратснижающие препараты в лечении подагры: неизвестное об известном. Научно-практическая ревматология. 2021;59(6):727-737. doi: 10.47360/1995-4484-2021-727-737.

33. Garanin A.A., Novichkova N.L., Novichkova N.L. Prospects of anti-inflammatory and urate-lowering therapy of gout: A vector from the past to the future. Rheumatology Science and Practice. 2022;60(2):205-213. (In Russ.) doi: 10.47360/1995-4484-2022-205-213.@@ Гаранин А.А., Новичкова Н.Л., Лебедев П.А. Перспективы противовоспалительной и уратснижающей терапии подагры: вектор от прошлого к будущему. Научно-практическая ревматология. 2022;60(2):205-213.

34. McWherter C., Choi Y.J., Serrano R.L. et al. Arhalofenate acid inhibits monosodium urate crystal-induced inflammatory responses through activation of AMPactivated protein kinase (AMPK) signaling. Arthritis Res Ther. 2018;20(1):204. doi: 10.1186/s13075-018-1699-4.

35. Klück V., Jansen T.L.T.A., Janssen M. et al. Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial. Lancet Rheumatol. 2020;2(5): e270-e280. doi: 10.1016/s2665-9913(20)30065-.

36. Schunk S.J., Kleber M.E., März W. eQTLGen consortium; BIOS consortium. Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality. Eur Heart J. 2021 May 7;42(18):1742-1756. doi: 10.1093/eurheartj/ehab107.

37. Olsen M.B., Gregersen I., Sandanger Ø. et al. Targeting the Inflammasome in Cardiovascular Disease. JACC Basic Transl Sci. 2021 Nov 3;7(1):84-98. doi: 10.1016/j.jacbts.2021.08.006.

38. Zhang H., Ma Y., Cao R. et al. Soluble uric acid induces myocardial damage through activating the NLRP3 inflammasome. J Cell Mol Med. 2020 Aug;24(15):8849-8861. doi: 10.1111/jcmm.15523.

39. Solomon D.H., Liu C-C., Kuo I-H. et al. Effects of colchicine on risk of cardiovascular events and mortality among patients with gout: a cohort study using electronic medical records linked with Medicare claims. Ann Rheum Dis. 2016;75:1674-1679. doi: 10.1136/annrheumdis-2015-207984.

40. Adler Y., Charron P., Imazio M. et al. ESC Guidelines for the diagnosis and management of pericardial diseases: the Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC) Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS) Eur Heart J. 2015;36:2921-2964. doi: 10.1093/eurheartj/ehv318.

41. Nidorf S.M., Eikelboom J.W., Budgeon C.A., Thompson P.L. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61:404-410. doi: 10.1016/j.jacc.2012.10.027.

42. Nidorf S.M., Fiolet A.T.L., Mosterd A. et al. LoDoCo2 Trial Investigators. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020 Nov 5;383(19):1838-1847. doi: 10.1056/NEJMoa2021372.

43. Bouabdallaoui N., Tardif J.C., Waters D.D. et al. Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Eur Heart J. 2020 Nov 7;41(42):4092-4099. doi: 10.1093/eurheartj/ehaa659.

44. Shvartz V., Le T., Enginoev S., Sokolskaya M. et al. Colchicine in Cardiac Surgery: The COCS Randomized Clinical Trial. J Cardiovasc Dev Dis. 2022 Oct 20;9(10):363. doi: 10.3390/jcdd9100363.

45. Solomon D.H., Glynn R.J., MacFadyen JG. et al. Relationship of Interleukin-1β Blockade With Incident Gout and Serum Uric Acid Levels: Exploratory Analysis of a Randomized Controlled Trial. Annals of Internal Medicine. 2018;169(8):535-42. doi: 10.7326/M18-1167.