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Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases.

ABSTRACT: Kynurenine pathway (KP) is the primary path of tryptophan (Trp) catabolism in most mammalian cells. The KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and 3-hydroxyanthranilic acid (3-HAA). Increased catabolite concentrations in serum are associated with several cardiovascular diseases (CVD), including heart disease, atherosclerosis, and endothelial dysfunction, as well as their risk factors, including hypertension, diabetes, obesity, and aging. The first catabolic step in KP is primarily controlled by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Following this first step, the KP has two major branches, one branch is mediated by kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU) and is responsible for the formation of 3-HK, 3-HAA, and quinolinic acid (QA); and another branch is controlled by kynurenine amino-transferase (KAT), which generates KA. Uncontrolled Trp catabolism has been demonstrated in distinct CVD, thus, understanding the underlying mechanisms by which regulates KP enzyme expression and activity is paramount. This review highlights the recent advances on the effect of KP enzyme expression and activity in different tissues on the pathological mechanisms of specific CVD, KP is an inflammatory sensor and modulator in the cardiovascular system, and KP catabolites act as the potential biomarkers for CVD initiation and progression. Moreover, the biochemical features of critical KP enzymes and principles of enzyme inhibitor development are briefly summarized, as well as the therapeutic potential of KP enzyme inhibitors against CVD is briefly discussed.

SUBMITTER: Song P

PROVIDER: S-EPMC5501999 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases.

Song Ping P Ramprasath Tharmarajan T Wang Huan H Zou Ming-Hui MH

Cellular and molecular life sciences : CMLS 20170317 16

Kynurenine pathway (KP) is the primary path of tryptophan (Trp) catabolism in most mammalian cells. The KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and 3-hydroxyanthranilic acid (3-HAA). Increased catabolite concentrations in serum are associated with several cardiovascular diseases (CVD), including heart disease, atherosclerosis, and endothelial dysfunction, as well as their risk factors, including ...[more]

PMID: 28314892

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Project description:Background Women with polycystic ovary syndrome (PCOS) suffer from dysfunctional metabolism and studies have reported increased levels of tryptophan in patients with PCOS. However, the changes of downstream metabolites in tryptophan catabolism pathways remain unclear. Methods This is a cross-sectional study that included 200 PCOS patients and 200 control women who were recruited from the Reproductive Medicine Center of Peking University Third Hospital from October 2017 to June 2019. The PCOS patients and the control group were further divided into subtypes of normal weight and overweight/obesity. Fasting blood samples from all subjects were collected on days 2~3 of a natural menstrual cycle or when amenorrhea for over 40 days with follicle diameter not exceeding 10 mm. The plasma levels of tryptophan metabolites were quantitatively determined by the liquid chromatograph mass spectrometer, including tryptophan, serotonin, kynurenine, kynurenic acid, 3-hydroxykynurenine, and quinolinic acid. Results The tryptophan-kynurenine pathway was dysregulated in women with PCOS, along with significantly elevated levels of tryptophan, serotonin, kynurenine, kynurenic acid, and quinolinic acid. Moreover, levels of tryptophan, kynurenine, and kynurenic acid were positively correlated with luteinizing hormone, anti-Müllerian hormone, fasting insulin, HOMA-IR. tryptophan, and kynurenine and quinolinic acid had an obvious association with C-reactive protein levels. Furthermore, logistic regression showed that tryptophan, serotonin, kynurenine, kynurenic acid and quinolinic acid were all associated significantly with the increased risk of PCOS with the adjustment for potential confounding factors. Additionally, tryptophan, kynurenine, and kynurenic acid had good diagnostic performances for PCOS, and their combination exhibited higher sensitivity and specificity to diagnostic efficiency, with the area under the ROC curve of 0.824 (95% CI 0.777-0.871), which was comparable to the endocrine indicators. Conclusion (s) The tryptophan-kynurenine pathway was abnormally activated in PCOS patients.

Project description:ObjectivePlasma kynurenine/tryptophan ratio, a biomarker of indoleamine 2,3-dioxygenase-1 (IDO) activity, is a strong independent predictor of mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART) and may play a key role in HIV pathogenesis. We performed a genome-wide study to identify potential host genetic determinants of kynurenine/tryptophan ratio in HIV-infected ART-suppressed Ugandans.Design/methodsWe performed genome-wide and exome array genotyping and measured plasma kynurenine/tryptophan ratio during the initial 6-12 months of suppressive ART in Ugandans. We evaluated more than 16 million single nucleotide polymorphisms in association with log10 kynurenine/tryptophan ratio using linear mixed models adjusted for cohort, sex, pregnancy, and ancestry.ResultsAmong 597 Ugandans, 62% were woman, median age was 35, median baseline CD4 cell count was 135 cells/μl, and median baseline HIV-1 RNA was 5.1 log10 copies/ml. Several polymorphisms in candidate genes TNF, IFNGR1, and TLR4 were associated with log10 kynurenine/tryptophan ratio (P < 5.0 × 10). An intergenic polymorphism between CSPG5 and ELP6 was genome-wide significant, whereas several others exhibited suggestive associations (P < 5.0 × 10), including genes encoding protein tyrosine phosphatases (PTPRM and PTPRN2) and the vitamin D metabolism gene, CYP24A1. Several of these single nucleotide polymorphisms were associated with markers of inflammation, coagulation, and monocyte activation, but did not replicate in a small US cohort (N = 262; 33% African-American).ConclusionOur findings highlight a potentially important role of IFN-γ, TNF-α, and Toll-like receptor signaling in determining IDO activity and subsequent mortality risk in HIV-infected ART-suppressed Ugandans. These results also identify potential novel pathways involved in IDO immunoregulation. Further studies are needed to confirm these findings in treated HIV-infected populations.

Project description:BackgroundInflammatory cytokine interleukin-6 (IL-6) plays a pivotal role in skeletal muscle degradation after intra-abdominal sepsis (IAS), with mechanism remained to be elucidated. Indoleamine 2,3-dioxygenase 1 (IDO-1), a key enzyme in converting tryptophan into kynurenine, could be activated by IL-6, and kynurenine has been shown to be involved in muscle degradation. We hypothesized that IL-6 could promote muscle degradation via tryptophan-IDO-1-kynurenine pathway in IAS patients.MethodsSerum and rectus abdominis (RA) were obtained from IAS or non-IAS patients. Mouse model of IAS-induced muscle wasting was generated by caecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection. IL-6 signalling was blocked by anti-mouse IL-6 antibody (IL-6-AB), and the IDO-1 pathway was blocked by navoximod. To elucidate the role of kynurenine in muscle mass and physiology, kynurenine was administered to IAS mice treated with IL-6-AB.ResultsCompared to non-IAS patients, kynurenine levels in serum (+2.30-fold vs. non-IAS, P < 0.001) and RA (+3.11-fold vs. non-IAS, P < 0.001) were elevated, whereas tryptophan levels in serum (-53.65% vs. non-IAS, P < 0.01) and RA (-61.39% vs. non-IAS, P < 0.01) were decreased. Serum IL-6 level of the IAS group was significantly higher compared to non-IAS patients (+5.82-fold vs. non-IAS, P = 0.01), and muscle cross-sectional area (MCSA) was markedly reduced compared to non-IAS patients (-27.73% vs. non-IAS, P < 0.01). In animal experiments, IDO-1 expression was up-regulated in the small intestine, colon and blood for CLP or LPS-treated mice, and there was correlation (R2 = 0.66, P < 0.01) between serum and muscle kynurenine concentrations. Navoximod significantly mitigated IAS-induced skeletal muscle loss according to MCSA analysis (+22.94% vs. CLP, P < 0.05; +23.71% vs. LPS, P < 0.01) and increased the phosphorylated AKT (+2.15-fold vs. CLP, P < 0.01; +3.44-fold vs. LPS, P < 0.01) and myosin heavy chain (+3.64-fold vs. CLP, P < 0.01; +2.13-fold vs. LPS, P < 0.01) protein expression in myocytes. In the presence of anti-IL-6 antibody, a significantly decreased IDO-1 expression was observed in the small intestine, colon and blood in CLP or LPS mice (all P < 0.01), whereas the decrease of MCSA was alleviated (+37.43% vs. CLP + IgG, P < 0.001; +30.72% vs. LPS + IgG, P < 0.001). In contrast, additional supplementation of kynurenine decreased the MCSA in septic mice treated with IL-6-AB (both P < 0.01).ConclusionsThis study provided novel insights into the tryptophan-IDO-1-kynurenine-dependent mechanisms that underlie inflammatory cytokine-induced skeletal muscle catabolism during intra-abdominal sepsis.

Project description:There is an increasing interest in the pathophysiological role of the kynurenine pathway of tryptophan metabolism in the regulation of immune function and inflammation. We sought to address the link between this pathway and the presence rheumatic diseases (RD) by conducting a systematic review and meta-analysis of studies reporting the plasma or serum concentrations of tryptophan, kynurenine, and other relevant metabolites in RD patients and healthy controls. We searched electronic databases for relevant articles published between inception and the 30th of June 2023. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and the Grades of Recommendation, Assessment, Development and Evaluation Working Group system. In 24 studies selected for analysis, compared to controls, RD patients had significantly lower tryptophan (standard mean difference, SMD= -0.71, 95% CI -1.03 to -0.39, p<0.001; I2 = 93.6%, p<0.001; low certainty of evidence), and higher kynurenine (SMD=0.69, 95% CI 0.35 to 1.02, p<0.001; I2 = 93.2%, p<0.001; low certainty), kynurenine to tryptophan ratios (SMD=0.88, 95% CI 0.55 to 1.21, p<0.001; I2 = 92.9%, p<0.001; moderate certainty), 3-hydroxykynurenine (SMD=0.74, 95% CI 0.30 to 1.18, p=0.001; I2 = 87.7%, p<0.001; extremely low certainty), and quinolinic acid concentrations (SMD=0.71, 95% CI 0.31 to 1.11, p<0.001; I2 = 88.1%, p<0.001; extremely low certainty). By contrast, there were non-significant between-group differences in kynurenic acid, 3-hydroxyanthranilic acid, kynurenic acid to kynurenine ratio, or quinolinic acid to kynurenine acid ratio. In meta-regression, the SMD of tryptophan, kynurenine, and kynurenine to tryptophan ratio were not associated with age, publication year, sample size, RD duration, C-reactive protein, or use of anti-rheumatic drugs and corticosteroids. In subgroup analysis, the SMD of tryptophan, kynurenine, and kynurenine to tryptophan ratio was significant across different types of RD, barring rheumatoid arthritis. Therefore, we have observed significant alterations in tryptophan, kynurenine, 3-hydroxykynurenine, and quinolinic acid concentrations in RD patients. Further research is warranted to determine whether these biomarkers can be useful for diagnosis and management in this patient group. (PROSPERO registration number: CRD CRD42023443718).Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD CRD42023443718.

Project description:Diabetic ketoacidosis (DKA) is a serious complication of complete insulin deficiency and insulin resistance in Type 1 diabetes (T1D). This results in the body producing high levels of serum ketones in an attempt to compensate for the insulin deficiency and decreased glucose utilization. DKA's metabolic and immunologic dysregulation results in gradual increase of systemic and cerebral oxidative stress, along with low grade systemic and cerebral inflammation and the development of pretreatment subclinical BE. During treatment the early progression of oxidative stress and inflammation is hypothesized to advance the possibility of occurrence of crisis of clinical brain edema (BE), which is the most important cause of morbidity and mortality in pediatric DKA. Longitudinal neurocognitive studies after DKA treatment show progressive and latent deficits of cognition and emphasize the need for more effective DKA treatment of this long-standing conundrum of clinical BE, in the presence of systemic osmotic dehydration, metabolic acidosis and immune dysregulation. Candidate biomarkers of several systemic and neuroinflammatory pathways prior to treatment also progress during treatment, such as the neurotoxic and neuroprotective molecules in the well-recognized tryptophan (TRP)/kynurenine pathway (KP) that have not been investigated in DKA. We used LC-MS/MS targeted mass spectrometry analysis to determine the presence and initiation of the TRP/KP at three time points: A) 6-12 hours after initiation of treatment; B) 2 weeks; and C) 3 months following DKA treatment to determine if they might be involved in the pathogenesis of the acute vasogenic complication of DKA/BE. The Trp/KP metabolites TRP, KYN, quinolinic acid (QA), xanthurnenic acid (XA), and picolinic acid (PA) followed a similar pattern of lower levels in early treatment, with subsequent increases. Time point A compared to Time points B and C were similar to the pattern of sRAGE, lactate and pyruvic acid. The serotonin/melatonin metabolites also followed a similar pattern of lower quantities at the early stages of treatment compared to 3 months after treatment. In addition, glutamate, n-acetylglutamate, glutamine, and taurine were all lower at early treatment compared to 3 months, while the ketones 3-hydroxybutaric acid and acetoacetate were significantly higher in the early treatment compared to 3 months. The two major fat metabolites, L-carnitine and acetyl-L-carnitine (ALC) changed inversely, with ALC significantly decreasing at 2 weeks and 3 months compared to the early stages of treatment. Both anthranilic acid (AA) and 3-OH-anthranilic acid (3OH-AA) had overall higher levels in the early stages of treatment (A) compared to Time points (B and C). Interestingly, the levels of AA and 3OH-AA early in treatment were higher in Caucasian females compared to African American females. There were also differences in the metabolite levels of QA and kynurenic acid (KA) between genders and between races that may be important for further development of custom targeted treatments. We hypothesize that the TRP/KP, along with the other inflammatory pathways, is an active participant in the metabolic and immunologic pathogenesis of DKA's acute and chronic insults.

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Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases.

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Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases.

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