Journal of Literature Pharmacy Sciences

Ateroskleroz Gelişim Sürecinde Kinürenin Yolağının Rolü: Geleneksel Derleme
The Role of the Kynurenine Pathway on the Developmental Process of Atherosclerosis: Traditional Review
Abdullah Burak KARADUMANa,b, Sinem ILGINa
aAnadolu Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji AD, Eskişehir, Türkiye
bHacettepe Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji AD, Ankara, Türkiye
J Lit Pharm Sci. 2024;13(2):117-23
doi: 10.5336/pharmsci.2024-101603
Article Language: TR
Full Text
ÖZET
Dünya genelinde ölümlerin başlıca nedeni olarak ifade edilen kardiyovasküler hastalıkların altında yatan etken genellikle aterosklerozdur. Ateroskleroz, intimal düşük yoğunluklu lipoprotein birikiminin artmasıyla başlayan ve endotel hücre geçirgenliğinin arttığı kronik inflamatuar bir durumdur. İnflamasyonun aterosklerotik olayların temel etkeni olduğu vurgulanmaktadır. Bilindiği gibi inflamasyon, vücudu enfeksiyonlara ve diğer hasarlara karşı koruyan ve iyileşmeyi destekleyen fizyolojik bir süreçtir. Ancak inflamatuar süreçler sırasında kalıcı immün reaksiyonlar aterosklerotik sürecin belirgin özelliğidir. Aterosklerozun farklı aşamalarında birçok immün sistem hücresi rol oynamaktadır. Son yıllarda, bazı amino asitlerin metabolik yolakları, inflamasyon ile ilgili mekanizmaların kontrolünde kritik kontrol noktaları olarak ifade edilmektedir. İmmün ve inflamatuar yanıtların önemli düzenleyicileri olarak ortaya çıkan farklı metabolik yolaklar arasında triptofan metabolizması kardiyovasküler hastalıkların gelişiminde önemli bir rol oynamaktadır. Triptofan metabolizmasındaki değişiklikler ile aterosklerozun başlangıcı ve ilerlemesi arasındaki ilişki tanımlanmıştır. Triptofan metabolizmasının %95'inden sorumlu olan metabolik yolak kinürenin yolağıdır. Sistemik düşük dereceli immün aracılıklı inflamasyon, interferon-γ gibi proinflamatuar sitokinlerin rol oynadığı aterosklerozda belirleyicidir. İnterferon-γ, indolamin 2,3-dioksijenaz enzimini yukarı regüle ederek triptofanın serum seviyelerini azaltmakta ve kinürenin yolağının metabolit düzeylerini artırmaktadır. Artan indolamin 2,3-dioksijenaz ekspresyonu ve aktivitesi ateroskleroz sürecini hızlandırmaktadır. Çalışmalar kinürenin yolağının biyoaktif metabolitlerinin ateroskleroz gelişiminde inflamatuar sürece katkısını göstermiştir. Bu derlemede, kinürenin yolağı temelinde triptofan metabolizması ve aterosklerotik kardiyovasküler hastalıklar arasındaki ilişkiye dikkat çeken güncel araştırmalar özetlemektedir.

Anahtar Kelimeler: Ateroskleroz; inflamasyon; triptofan metabolizması; kinürenin yolağı
ABSTRACT
The underlying factor behind cardiovascular diseases, which are commonly cited as the primary cause of death worldwide, is usually atherosclerosis. Atherosclerosis is a chronic inflammatory condition characterized by increased intimal low-density lipoprotein deposition and increased endothelial cell permeability. It is emphasized that inflammation is the main factor of atherosclerotic events. As is known, inflammation is a physiological process that protects the body against infections and other injuries and supports healing. Persistent immune reactions during inflammatory processes are a characteristic feature of the atherosclerotic process. Various stages of atherosclerosis involve the participation of numerous immune system cells. In recent years, certain amino acid metabolic pathways have been identified as critical control points in controlling inflammation-related mechanisms. The metabolism of tryptophan among different metabolic pathways, emerging as significant regulators of immune and inflammatory responses, plays an important role in developing cardiovascular diseases. The relationship between changes in tryptophan metabolism and the initiation and progression of atherosclerosis has been defined. The metabolic pathway responsible for approximately 95% of tryptophan metabolism is the kynurenine pathway. Systemic low-grade immunemediated inflammation is a hallmark of atherosclerosis in which proinflammatory cytokines such as interferon-γ play a role. Interferon-γ decreases serum levels of tryptophan and increases levels of metabolites of the kynurenine pathway by upregulating the indoleamine 2,3-dioxygenase enzyme. Increased indoleamine 2,3-dioxygenase enzyme expression and activity accelerate the atherosclerosis process. Studies have shown that bioactive metabolites of the kynurenine pathway contribute to the inflammatory process in the development of atherosclerosis. In this review, current research is summarized, highlighting the relationship between tryptophan metabolism and atherosclerotic cardiovascular disease based on the kynurenine pathway.

Keywords: Atherosclerosis; inflammation; tryptophan metabolism; kynurenine pathway
REFERENCES:
  1. Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nat Rev Dis Primers. 2019;5(1):56. [Crossref]  [PubMed] 
  2. Teunis CJ, Stroes ESG, Boekholdt SM, Wareham NJ, Murphy AJ, Nieuwdorp M, et al. Tryptophan metabolites and incident cardiovascular disease: The EPIC-Norfolk prospective population study. Atherosclerosis. 2023;387:117344. [Crossref]  [PubMed] 
  3. Bays HE, Taub PR, Epstein E, Michos ED, Ferraro RA, Bailey AL, et al. Ten things to know about ten cardiovascular disease risk factors. Am J Prev Cardiol. 2021;5:100149. [Crossref]  [PubMed]  [PMC] 
  4. Nishimura M, Yamashita A, Matsuura Y, Okutsu J, Fukahori A, Hirata T, et al. Upregulated kynurenine pathway enzymes in aortic atherosclerotic aneurysm: macrophage kynureninase downregulates inflammation. J Atheroscler Thromb. 2021;28(11):1214-40. [Crossref]  [PubMed]  [PMC] 
  5. Ala M, Eftekhar SP. The footprint of kynurenine pathway in cardiovascular diseases. Int J Tryptophan Res. 2022;15:11786469221096643. [Crossref]  [PubMed]  [PMC] 
  6. Mallika V, Goswami B, Rajappa M. Atherosclerosis pathophysiology and the role of novel risk factors: a clinicobiochemical perspective. Angiology. 2007;58(5):513-22. [Crossref]  [PubMed] 
  7. Alfarisi HAH, Mohamed ZBH, Bin IM. Basic pathogenic mechanisms of atherosclerosis. Egypt J Basic Appl Sci. 2020;7(1):116-25. [Crossref] 
  8. Binder CJ, Chang MK, Shaw PX, Miller YI, Hartvigsen K, Dewan A, et al. Innate and acquired immunity in atherogenesis. Nat Med. 2002;8(11):1218-26. [Crossref]  [PubMed] 
  9. Baumgartner R, Berg M, Matic L, Polyzos KP, Forteza MJ, Hjorth SA, et al. Evidence that a deviation in the kynurenine pathway aggravates atherosclerotic disease in humans. J Intern Med. 2021;289(1):53-68. [Crossref]  [PubMed] 
  10. Pahwa R, Jialal I. Atherosclerosis. 2023 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. [PubMed] 
  11. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114(12):1852-66. [Crossref]  [PubMed] 
  12. Rafieian-Kopaei M, Setorki M, Doudi M, Baradaran A, Nasri H. Atherosclerosis: process, indicators, risk factors and new hopes. Int J Prev Med. 2014;5(8):927-46. [PubMed]  [PMC] 
  13. Melhem NJ, Taleb S. Tryptophan: from diet to cardiovascular diseases. Int J Mol Sci. 2021;22(18):9904. [Crossref]  [PubMed]  [PMC] 
  14. Fatkhullina AR, Peshkova IO, Koltsova EK. The role of cytokines in the development of atherosclerosis. Biochemistry (Mosc). 2016;81(11):1358-70. [Crossref]  [PubMed]  [PMC] 
  15. Baumgartner R, Forteza MJ, Ketelhuth DFJ. The interplay between cytokines and the Kynurenine pathway in inflammation and atherosclerosis. Cytokine. 2019;122:154148. [Crossref]  [PubMed] 
  16. Tousoulis D, Oikonomou E, Economou EK, Crea F, Kaski JC. Inflammatory cytokines in atherosclerosis: current therapeutic approaches. Eur Heart J. 2016;37(22):1723-32. [Crossref]  [PubMed] 
  17. Theiler-Schwetz V, Trummer C, Grübler MR, Keppel MH, Zittermann A, Tomaschitz A, et al. Associations of parameters of the tryptophan-kynurenine pathway with cardiovascular risk factors in hypertensive patients. Nutrients. 2023;15(2):256. [Crossref]  [PubMed]  [PMC] 
  18. Berg M, Polyzos KA, Agardh H, Baumgartner R, Forteza MJ, Kareinen I, et al. 3-Hydroxyanthralinic acid metabolism controls the hepatic SREBP/lipoprotein axis, inhibits inflammasome activation in macrophages, and decreases atherosclerosis in Ldlr-/- mice. Cardiovasc Res. 2020;116(12):1948-57. [Crossref]  [PubMed]  [PMC] 
  19. Schröcksnadel K, Wirleitner B, Winkler C, Fuchs D. Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta. 2006;364(1-2):82-90. [Crossref]  [PubMed] 
  20. Savitz J. The kynurenine pathway: a finger in every pie. Mol Psychiatry. 2020;25(1):131-47. [Crossref]  [PubMed]  [PMC] 
  21. Yu F, Du Y, Li C, Zhang H, Lai W, Li S, et al. Association between metabolites in tryptophan-kynurenine pathway and inflammatory bowel disease: a two-sample Mendelian randomization. Sci Rep. 2024;14(1):201. [Crossref]  [PubMed]  [PMC] 
  22. Harris DMM, Szymczak S, Schuchardt S, Labrenz J, Tran F, Welz L, et al. Tryptophan degradation as a systems phenomenon in inflammation - an analysis across 13 chronic inflammatory diseases. EBioMedicine. 2024;102:105056. [Crossref]  [PubMed]  [PMC] 
  23. Uçar T, Cansever MŞ, Isat E, Zubarioğlu T, Aktuğlu Zeybek AÇ, Topçu B, et al. Serum neopterin, biopterin, tryptophan, and kynurenine levels in patients with fabry disease. Balkan Med J. 2024;41(2):113-20. [Crossref]  [PubMed]  [PMC] 
  24. Shi Y, Luo S, Zhai J, Chen Y. A novel causative role of imbalanced kynurenine pathway in ulcerative colitis: upregulation of KMO and KYNU promotes intestinal inflammation. Biochim Biophys Acta Mol Basis Dis. 2024;1870(2):166929. [Crossref]  [PubMed] 
  25. Eryavuz Onmaz D, Tezcan D, Abusoglu S, Sivrikaya A, Kuzu M, Yerlikaya FH, et al. Elevated serum levels of kynurenine pathway metabolites in patients with Behçet disease. Amino Acids. 2022;54(6):877-87. [Crossref]  [PubMed] 
  26. Cihan M, Doğan Ö, Ceran Serdar C, Altunçekiç Yıldırım A, Kurt C, Serdar MA. Kynurenine pathway in coronavirus disease (COVID-19): potential role in prognosis. J Clin Lab Anal. 2022;36(3):e24257. [Crossref]  [PubMed]  [PMC] 
  27. Wang M, Dong X, Huang Y, Su J, Dai X, Guo Y, et al. Activation of the kynurenine pathway is associated with poor outcome in Pneumocystis pneumonia patients infected with HIV: results of 2 months cohort study. BMC Infect Dis. 2019;19(1):223. [Crossref]  [PubMed]  [PMC] 
  28. Bedel HA, Coşkun A, Usta C. Kinürenin yolağı ve ilişkili nörodejeneratif hastalıklar [Kynurenine pathway and related neurodegenerative disorders]. Turkiye Klinikleri J Neur. 2018;13(2):35-46. [Crossref] 
  29. Badawy AA. Tryptophan metabolism: a versatile area providing multiple targets for pharmacological intervention. Egypt J Basic Clin Pharmacol. 2019;9:10.32527/2019/101415. [Crossref]  [PubMed]  [PMC] 
  30. Sadok I, Gamian A, Staniszewska MM. Chromatographic analysis of tryptophan metabolites. J Sep Sci. 2017;40(15):3020-45. Erratum in: J Sep Sci. 2018;41(9):2102. [Crossref]  [PubMed]  [PMC] 
  31. Tsuji A, Ikeda Y, Yoshikawa S, Taniguchi K, Sawamura H, Morikawa S, et al. The Tryptophan and kynurenine pathway involved in the development of immune-related diseases. Int J Mol Sci. 2023;24(6):5742. [Crossref]  [PubMed]  [PMC] 
  32. Gáspár R, Halmi D, Demján V, Berkecz R, Pipicz M, Csont T. Kynurenine pathway metabolites as potential clinical biomarkers in coronary artery disease. Front Immunol. 2022;12:768560. [Crossref]  [PubMed]  [PMC] 
  33. Kember I, Girgin G, Baydar T. Neopterin düzeylerinin ve kinürenin yolağının akut koroner sendrom hastalarında değerlendirilmesi [Evaluation of neopterin levels and kynurenine pathway in acute coronary syndrome patients]. Hacettepe University Journal of the Faculty of Pharmacy. 2023;43(4):340-51. [Link] 
  34. Mangge H, Reininghaus E, Fuchs D. Role of kynurenine pathway in cardiovascular diseases. In: Mittal S, ed. Targeting the Broadly Pathogenic Kynurenine Pathway. Cham: Springer; 2015. p.133-45. [Crossref] 
  35. Benitez T, VanDerWoude E, Han Y, Byun J, Konje VC, Gillespie BW, et al. Kynurenine pathway metabolites predict subclinical atherosclerotic disease and new cardiovascular events in chronic kidney disease. Clin Kidney J. 2022;15(10):1952-65. [Crossref]  [PubMed]  [PMC] 
  36. Song P, Ramprasath T, Wang H, Zou MH. Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases. Cell Mol Life Sci. 2017;74(16):2899-916. [Crossref]  [PubMed]  [PMC] 
  37. Jasiewicz M, Moniuszko M, Pawlak D, Knapp M, Rusak M, Kazimierczyk R, al. Activity of the kynurenine pathway and its interplay with immunity in patients with pulmonary arterial hypertension. Heart. 2016;102(3):230-7. [Crossref]  [PubMed] 
  38. Wang Q, Liu D, Song P, Zou MH. Tryptophan-kynurenine pathway is dysregulated in inflammation, and immune activation. Front Biosci (Landmark Ed). 2015;20(7):1116-43. [Crossref]  [PubMed]  [PMC] 
  39. Sulo G, Vollset SE, Nygård O, Midttun Ø, Ueland PM, Eussen SJ, et al. Neopterin and kynurenine-tryptophan ratio as predictors of coronary events in older adults, the Hordaland Health Study. Int J Cardiol. 2013;168(2):1435-40. [Crossref]  [PubMed] 
  40. Niinisalo P, Oksala N, Levula M, Pelto-Huikko M, Järvinen O, Salenius JP, et al. Activation of indoleamine 2,3-dioxygenase-induced tryptophan degradation in advanced atherosclerotic plaques: tampere vascular study. Ann Med. 2010;42(1):55-63. [Crossref]  [PubMed] 
  41. Niinisalo P, Raitala A, Pertovaara M, Oja SS, Lehtimäki T, Kähönen M, et al. Indoleamine 2,3-dioxygenase activity associates with cardiovascular risk factors: the Health 2000 study. Scand J Clin Lab Invest. 2008;68(8):767-70. [Crossref]  [PubMed] 
  42. Pertovaara M, Raitala A, Juonala M, Lehtimäki T, Huhtala H, Oja SS, et al. Indoleamine 2,3-dioxygenase enzyme activity correlates with risk factors for atherosclerosis: the Cardiovascular Risk in Young Finns Study. Clin Exp Immunol. 2007;148(1):106-11. [Crossref]  [PubMed]  [PMC] 
  43. Wirleitner B, Rudzite V, Neurauter G, Murr C, Kalnins U, Erglis A, et al. Immune activation and degradation of tryptophan in coronary heart disease. Eur J Clin Invest. 2003;33(7):550-4. [Crossref]  [PubMed] 
  44. Kember I, Sanajou S, Kilicarslan B, Girgin G, Baydar T. Evaluation of neopterin levels and kynurenine pathway in patients with acute coronary syndrome. Acute Crit Care. 2023;38(3):325-32. [Crossref]  [PubMed]  [PMC] 
  45. Liang H, Chen M, Qi F, Shi L, Duan Z, Yang R, et al. The proatherosclerotic function of indoleamine 2, 3-dioxygenase 1 in the developmental stage of atherosclerosis. Signal Transduct Target Ther. 2019;4:23. [Crossref]  [PubMed]  [PMC] 
  46. Razquin C, Ruiz-Canela M, Toledo E, Clish CB, Guasch-Ferré M, García-Gavilán JF, et al. Circulating amino acids and risk of peripheral artery disease in the PREDIMED trial. Int J Mol Sci. 2022;24(1):270. [Crossref]  [PubMed]  [PMC] 
  47. Kozhevnikova MV, Krivova AV, Korobkova EO, Ageev AA, Shestakova KM, Moskaleva NE, et al. Comparative analysis of tryptophan and downstream metabolites of the kynurenine and serotonin pathways in patients with arterial hypertension and coronary artery disease. Kardiologiia. 2022;62(11):40-8. Russian, English. [Crossref]  [PubMed] 
  48. Zapolski T, Kamińska A, Kocki T, Wysokiński A, Urbanska EM. Aortic stiffness-Is kynurenic acid a novel marker? Cross-sectional study in patients with persistent atrial fibrillation. PLoS One. 2020;15(7):e0236413. [Crossref]  [PubMed]  [PMC] 
  49. Eussen SJ, Ueland PM, Vollset SE, Nygård O, Midttun Ø, Sulo G, et al. Kynurenines as predictors of acute coronary events in the Hordaland Health Study. Int J Cardiol. 2015;189:18-24. [Crossref]  [PubMed] 
  50. Pedersen ER, Midttun Ø, Ueland PM, Schartum-Hansen H, Seifert R, Igland J, et al. Systemic markers of interferon-γ-mediated immune activation and long-term prognosis in patients with stable coronary artery disease. Arterioscler Thromb Vasc Biol. 2011;31(3):698-704. [Crossref]  [PubMed] 
  51. Zuo H, Ueland PM, Ulvik A, Eussen SJ, Vollset SE, Nygård O, et al. Plasma biomarkers of inflammation, the kynurenine pathway, and risks of all-cause, cancer, and cardiovascular disease mortality: the hordaland health study. Am J Epidemiol. 2016;183(4):249-58. [Crossref]  [PubMed]  [PMC] 

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5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com