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

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.

Increased uptake of oxLDL does not exert lipotoxic effects in insulin-secreting cells.

Modified lipoproteins can negatively affect beta cell function and survival. However, the mechanisms behind interactions of modified lipoproteins with beta cells - and in particular, relationships to increased uptake - are only partly clarified. By over-expressing the scavenger receptor CD36 (Tet-on), we increased the uptake of fluorescent low-density modified lipoprotein (oxLDL) into insulin-secreting INS-1 cells. The magnitude of uptake followed the degree of CD36 over-expression. CD36 over-expression increased concomitant efflux of 3H-cholesterol in proportion to the cellular contents of 3H-cholesterol. Exposure to concentrations of oxLDL from 20 to 100 µg/mL dose-dependently increased toxicity (evaluated by MTT) as well as apoptosis. However, the increased uptake of oxLDL due to CD36 over-expression did not exert additive effects on oxLDL toxicity - neither on viability, nor on glucose-induced insulin release and cellular content. Reciprocally, blocking CD36 receptors by Sulfo-N-Succinimidyl Oleate decreased the uptake of oxLDL but did not diminish the toxicity. Pancreatic islets of CD36-/- mice displayed reduced uptake of 3H-cholesterol-labeled oxLDL vs wild type but similar toxicity to oxLDL. OxLDL was found to increase the expression of CD36 in islets and INS-1 cells. In summary, given the experimental conditions, our results indicate that (1) increased uptake of oxLDL is not responsible for toxicity of oxLDL, (2) increased efflux of the cholesterol moiety of oxLDL counterbalances, at least in part, increased uptake and (3) oxLDL participates in the regulation of CD36 in pancreatic islets and in INS-1 cells.

Alteración de los sistemas antinociceptivos en las cefaleas crónicas diarias / Alteration of the antinociceptive systems in chronic daily headaches

Introducción. La cefalea crónica diaria (CCD) es un cuadrodoloroso crónico frecuente en la práctica neurológica. El diagnósticoes clínico y el abordaje terapéutico resulta complejo. No estáclaro todavía cuál es su mecanismo de producción, pero se reconoceun componente genético como factor predisponente. Son múltipleslas áreas que participan en la generación de cefaleas primarias,entre las que se encuentra la sustancia gris periacueductal (SGPA),que participa como neuromoduladora tanto en cefaleas como enotros cuadros dolorosos crónicos. Objetivos. Para evaluar posiblescambios bioquímicos en pacientes con CCD se estudiaron los espectrospor resonancia magnética en la SGPA. Sujetos y métodos. Seestudiaron los espectros en la SGPA en 17 pacientes con CCD y secompararon con el espectro promedio de 17 sujetos sanos a travésdel análisis espectroscópico diferencial. Resultados. Los sujetos conCCD presentan una reducción mayor del 70% del metabolito N-acetilaspartato glutamato (NAAG) en la SGPA. El NAAG es un péptidorelacionado con actividad antinociceptiva. Conclusión. La reduccióndel NAAG en la SPGA sugiere una alteración de la neuromodulaciónde sistemas antinociceptivos en sujetos con CCD. Queda pendientede que se establezca si la CCD es la causa o la consecuencia

Introduction. Chronic daily headache (CDH) is a chronic painful clinical condition that is frequently found inneurological practice. Diagnosis is clinical and the therapeutic approach is complex. Its mechanism of production is still notaltogether clear, but a genetic component is acknowledged as a predisposing factor. Numerous areas are involved in thegeneration of primary headaches, including the periaqueductal grey matter (PAGM), which plays a role as a neuromodulatorboth in headaches and in other chronic painful conditions. Aims. In order to evaluate possible biochemical changes inpatients with CDH, magnetic resonance imaging was used to study the spectra produced in the PAGM. Subjects and methods.The spectra in the PAGM were studied in 17 patients with CDH. These were compared with the average spectra in 17 healthysubjects by means of differential spectroscopy. Results. Subjects with CDH show a reduction of over 70% in the level of themetabolite N-acetyl-aspartyl-glutamate (NAAG) in the PAGM. NAAG is a peptide involved in antinociceptive activity. Conclusions.The reduction of NAAG in the PAGM suggests altered neuromodulation of the antinociceptive systems in subjects with CDH.Whether CDH is the cause or the consequence has still to be determined

[Alteration of the antinociceptive systems in chronic daily headaches]. / Alteracion de los sistemas antinociceptivos en las cefaleas cronicas diarias.

INTRODUCTION: Chronic daily headache (CDH) is a chronic painful clinical condition that is frequently found in neurological practice. Diagnosis is clinical and the therapeutic approach is complex. Its mechanism of production is still not altogether clear, but a genetic component is acknowledged as a predisposing factor. Numerous areas are involved in the generation of primary headaches, including the periaqueductal grey matter (PAGM), which plays a role as a neuromodulator both in headaches and in other chronic painful conditions. AIMS: In order to evaluate possible biochemical changes in patients with CDH, magnetic resonance imaging was used to study the spectra produced in the PAGM. SUBJECTS AND METHODS: The spectra in the PAGM were studied in 17 patients with CDH. These were compared with the average spectra in 17 healthy subjects by means of differential spectroscopy. RESULTS: Subjects with CDH show a reduction of over 70% in the level of the metabolite N-acetyl-aspartyl-glutamate (NAAG) in the PAGM. NAAG is a peptide involved in antinociceptive activity. CONCLUSIONS: The reduction of NAAG in the PAGM suggests altered neuromodulation of the antinociceptive systems in subjects with CDH. Whether CDH is the cause or the consequence has still to be determined.