ArticleCirculation research2014
Activation of NAD(P)H oxidase by tryptophan-derived 3-hydroxykynurenine accelerates endothelial apoptosis and dysfunction in vivo.
Article in Circulation research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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Who cites it
73 citing papers in PubMed, 115 citations in OpenAlex.
- VSMC-derived 3HAA activates AhR to drive abdominal aortic aneurysm formation via the p62-Nrf2 axis.Redox biology · 2026Article
- Tryptophan Metabolism in Cardiometabolic Diseases: Focus on the Kynurenine Pathway.International journal of molecular sciences · 2026Review
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- Metabolic adaptations rewire CD4Nature immunology · 2026Article
- Integrated fetal testicular transcriptomic and epigenomic profiles during maternal nutrient restriction with dietary melatonin intervention.Journal of animal science · 2026Article
- Rapid LC-MS/MS-based quantitative serum tryptophan metabolomics platform identifies and monitors novel biomarkers for diabetic kidney disease.Analytical and bioanalytical chemistry · 2026Article
- The Kynurenine Metabolite 3-Hydroxykynurenine is Associated With Risk of Heart Failure in Patients With Predominantly Stable Coronary Artery Disease.International journal of tryptophan research : IJTR · 2026Article
- The Role of Downstream Kynurenine Pathway Metabolites in the Modulation of Cardiovascular Disease Development in Chronic Kidney Disease.International journal of tryptophan research : IJTR · 2026Review
- Review
- Perturbed pediatric circulating metabolome in mild and severe dengue disease.Journal of virology · 2025Article
- Glucocorticoid-Mediated Skeletal Muscle Atrophy: Molecular Mechanisms and Potential Therapeutic Targets.International journal of molecular sciences · 2025Review
- Pregnancy complications affect kynurenine pathway metabolite concentrations in umbilical cord blood.Reproductive biology and endocrinology : RB&E · 2025Article
- A Narrative Review of Biomarkers and Imaging in the Diagnosis of Acute Aortic Syndrome.Diagnostics (Basel, Switzerland) · 2025Review
- Flavins and Flavoproteins in the Neuroimmune Landscape of Stress Sensitization and Major Depressive Disorder.Journal of inflammation research · 2025Review
- Fructose-1,6-bisphosphate reverses hypotensive effect caused by L-kynurenine in Wistar male rats.Physiological reports · 2024Article
- Progress and perspectives of metabolic biomarkers in human aortic dissection.Metabolomics : Official journal of the Metabolomic Society · 2024Review
- First trimester maternal tryptophan metabolism and embryonic and fetal growth: the Rotterdam Periconceptional Cohort (Predict Study).Human reproduction (Oxford, England) · 2024Observational
- The gut microbiome as a modulator of arterial function and age-related arterial dysfunction.American journal of physiology. Heart and circulatory physiology · 2024Review
- Kynurenine pathway and its role in neurologic, psychiatric, and inflammatory bowel diseases.Molecular biology reports · 2023Review
- FUS regulates the alternative splicing of cell proliferation genes related to atherosclerosis.Experimental biology and medicine (Maywood, N.J.) · 2023Article
13 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
rationaleThe kynurenine (Kyn) pathway is the major route for tryptophan (Trp) metabolism in mammals. The Trp-Kyn pathway is reported to regulate several fundamental biological processes, including cell death.
objectiveThe aim of this study was to elucidate the contributions and molecular mechanism of Trp-Kyn pathway to endothelial cell death. METHODS AND
resultsEndogenous reactive oxygen species, endothelial cell apoptosis, and endothelium-dependent and endothelium-independent vasorelaxation were measured in aortas of wild-type mice or mice deficient for nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase subunits (p47(phox) or gp91(phox)) or indoleamine-pyrrole 2,3-dioxygenase 1 with or without angiotensin (Ang) II infusion. As expected, AngII increased plasma levels of Kyn- and 3-hydroxykynurenine-modified proteins in endothelial cells in vivo. Consistent with this, AngII markedly increased the expression of indoleamine-pyrrole 2,3-dioxygenase in parallel with increased expression of interferon-γ. Furthermore, in wild-type mice, AngII significantly increased oxidative stress, endothelial cell apoptosis, and endothelial dysfunction. These effects of AngII infusion were significantly suppressed in mice deficient for p47(phox), gp91(phox), or indoleamine-pyrrole 2,3-dioxygenase 1, suggesting that AngII-induced enhancement of Kynurenines via NAD(P)H oxidase-derived oxidants causes endothelial cell apoptosis and dysfunction in vivo. Furthermore, interferon-γ neutralization eliminates AngII-increased superoxide products and endothelial apoptosis by inhibiting AngII-induced Kynurenines generation, suggesting that AngII-activated Kyn pathway is interferon-γ-dependent. Mechanistically, we found that AngII-enhanced 3-hydroxykynurenine promoted the generation of NAD(P)H oxidase-mediated superoxide anions by increasing the translocation and membrane assembly of NAD(P)H oxidase subunits in endothelial cells, resulting in accelerated apoptosis and consequent endothelial dysfunction.
conclusionsKyn pathway activation accelerates apoptosis and dysfunction of the endothelium by upregulating NAD(P)H-derived superoxide.
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