Evidence that a deviation in the kynurenine pathway aggravates atherosclerotic disease in humans

Autor: Thue W. Schwartz, Ulf Hedin, Roland Baumgartner, Daniel F. J. Ketelhuth, Siv A. Hjorth, Göran K. Hansson, Ljubica Perisic Matic, Gabrielle Paulsson-Berne, K P Polyzos, Martin Berg, Maria J. Forteza
Rok vydání: 2020
Předmět:
ARYL-HYDROCARBON RECEPTOR
Carotid Artery Diseases
0301 basic medicine
Kynurenine pathway
INHIBITION
Regulator
Down-Regulation
Inflammation
030204 cardiovascular system & hematology
Pharmacology
Kynurenic Acid
CORONARY EVENTS
IDO
ACTIVATION
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Kynurenic acid
Downregulation and upregulation
kynurenic acid
In vivo
Internal Medicine
medicine
Humans
Macrophage
REGULATORY T-CELLS
Kynurenine
biology
aryl hydrocarbon receptor
business.industry
CARDIOVASCULAR RISK
Macrophages
Tryptophan
Aryl hydrocarbon receptor
Plaque
Atherosclerotic

TRYPTOPHAN
Up-Regulation
030104 developmental biology
chemistry
QUINOLINIC ACID
inflammation
biology.protein
atherosclerosis
medicine.symptom
business
INDOLEAMINE 2
3-DIOXYGENASE

kynurenine pathway
Zdroj: Baumgartner, R, Berg, M, Matic, L, Polyzos, K P, Forteza, M J, Hjorth, S A, Schwartz, T W, Paulson-Berne, G, Hansson, G K, Hedin, U & Ketelhuth, D F J 2021, ' Evidence that a deviation in the kynurenine pathway aggravates atherosclerotic disease in humans ', Journal of Internal Medicine, vol. 289, no. 1, pp. 53-68 . https://doi.org/10.1111/joim.13142
ISSN: 1365-2796
0954-6820
DOI: 10.1111/joim.13142
Popis: BACKGROUND: The metabolism of tryptophan (Trp) along the kynurenine pathway has been shown to carry strong immunoregulatory properties. Several experimental studies indicate that this pathway is a major regulator of vascular inflammation and influences atherogenesis. Knowledge of the role of this pathway in human atherosclerosis remains incomplete.OBJECTIVES: In this study, we performed a multiplatform analysis of tissue samples, in vitro and in vivo functional assays to elucidate the potential role of the kynurenine pathway in human atherosclerosis.METHODS AND RESULTS: Comparison of transcriptomic data from carotid plaques and control arteries revealed an upregulation of enzymes within the quinolinic branch of the kynurenine pathway in the disease state, whilst the branch leading to the formation of kynurenic acid (KynA) was downregulated. Further analyses indicated that local inflammatory responses are closely tied to the deviation of the kynurenine pathway in the vascular wall. Analysis of cerebrovascular symptomatic and asymptomatic carotid stenosis data showed that the downregulation of KynA branch enzymes and reduced KynA production were associated with an increased probability of patients to undergo surgery due to an unstable disease. In vitro, we showed that KynA-mediated signalling through aryl hydrocarbon receptor (AhR) is a major regulator of human macrophage activation. Using a mouse model of peritoneal inflammation, we showed that KynA inhibits leukocyte recruitment.CONCLUSIONS: We have found that a deviation in the kynurenine pathway is associated with an increased probability of developing symptomatic unstable atherosclerotic disease. Our study suggests that KynA-mediated signalling through AhR is an important mechanism involved in the regulation of vascular inflammation.
Databáze: OpenAIRE