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The main risk factor is elevated intraocular pressure (IOP), but the actual cause of the disease remains unknown. Emerging evidence indicates that metabolic dysfunction plays a central role. The aim of the current study was to determine and compare the effect of universal hypoxia on the metabolomic signature in plasma samples from healthy controls (n = 10), patients with normal-tension glaucoma (NTG, n = 10), and ocular hypertension (OHT, n = 10). By subjecting humans to universal hypoxia, we aim to mimic a state in which the mitochondria in the body are universally stressed. Participants were exposed to normobaric hypoxia for two hours, followed by a 30 min recovery period in normobaric normoxia. Blood samples were collected at baseline, during hypoxia, and in recovery. Plasma samples were analyzed using a non-targeted metabolomics approach based on liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). Multivariate analyses were conducted using principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), and univariate analysis using the Wilcoxon signed-rank test and false discovery rate (FDR) correction. Unique metabolites involved in fatty acid biosynthesis and ketone body metabolism were upregulated, while metabolites of the kynurenine pathway were downregulated in OHT patients exposed to universal hypoxia. Differential affection of metabolic pathways may explain why patients with OHT initially do not suffer or are more resilient from optic nerve degeneration. The metabolomes of NTG and OHT patients are regulated differently from control subjects and show dysregulation of metabolites important for energy production. These dysregulated processes may potentially contribute to the elevation of IOP and, ultimately, cell death of the RGCs.<\/jats:p>","DOI":"10.3390\/ijms25010195","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T08:53:01Z","timestamp":1703235181000},"page":"195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Distinct Metabolic Profiles of Ocular Hypertensives in Response to Hypoxia"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4107-8990","authenticated-orcid":false,"given":"Mia","family":"Langb\u00f8l","sequence":"first","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4114-0267","authenticated-orcid":false,"given":"Jens","family":"Rovelt","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark"},{"name":"Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, 2600 Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arevak","family":"Saruhanian","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7143-7654","authenticated-orcid":false,"given":"Sarkis","family":"Saruhanian","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark"},{"name":"Department of Veterinary & Animal Sciences, University of Copenhagen, 2000 Frederiksberg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Tiedemann","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark"},{"name":"Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, 2600 Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thisayini","family":"Baskaran","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8822-9832","authenticated-orcid":false,"given":"Cinzia","family":"Bocca","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de Sant\u00e9, Institut MITOVASC, UMR CNRS 6015, INSERM U1083, Universit\u00e9 d\u2019Angers, 49933 Angers, France"},{"name":"D\u00e9partement de Biochimie et Biologie Mol\u00e9culaire, Centre Hospitalier Universitaire (CHU), 49933 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupali","family":"Vohra","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark"},{"name":"Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, 2600 Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7402-1854","authenticated-orcid":false,"given":"Barbara","family":"Cvenkel","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2736-3349","authenticated-orcid":false,"given":"Guy","family":"Lenaers","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de Sant\u00e9, Institut MITOVASC, UMR CNRS 6015, INSERM U1083, Universit\u00e9 d\u2019Angers, 49933 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8697-0734","authenticated-orcid":false,"given":"Miriam","family":"Kolko","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark"},{"name":"Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, 2600 Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1136\/bjophthalmol-2015-307223","article-title":"Global variations and time trends in the prevalence of primary open angle glaucoma (POAG): A systematic review and meta-analysis","volume":"100","author":"Kapetanakis","year":"2016","journal-title":"Br. 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