Distinct Metabolic Profiles of Ocular Hypertensives in Response to Hypoxia

IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Molecular Sciences Pub Date : 2023-12-22 DOI:10.3390/ijms25010195
Mia Langbøl, Jens Rovelt, Arevak Saruhanian, Sarkis Saruhanian, Daniel Tiedemann, Thisayini Baskaran, C. Bocca, R. Vohra, B. Cvenkel, G. Lenaers, M. Kolko
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Abstract

Glaucoma is a neurodegenerative disease that affects the retinal ganglion cells (RGCs). 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.
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眼部高血压患者对缺氧反应的不同代谢特征
青光眼是一种影响视网膜神经节细胞(RGC)的神经退行性疾病。主要风险因素是眼内压(IOP)升高,但真正的病因仍不清楚。新的证据表明,代谢功能障碍在其中起着核心作用。本研究旨在确定和比较普遍缺氧对健康对照组(10 人)、正常张力青光眼(NTG,10 人)和眼高压症(OHT,10 人)血浆样本代谢组特征的影响。通过让人体处于普遍缺氧状态,我们旨在模拟体内线粒体普遍受压的状态。参与者在常压缺氧状态下暴露 2 小时,然后在常压正常缺氧状态下恢复 30 分钟。在基线期、缺氧期和恢复期采集血液样本。血浆样本采用基于液相色谱耦合高分辨质谱(LC-HRMS)的非靶向代谢组学方法进行分析。使用主成分分析(PCA)和正交偏最小二乘判别分析(OPLS-DA)进行了多变量分析,并使用Wilcoxon符号秩检验和错误发现率(FDR)校正进行了单变量分析。在暴露于普遍缺氧的 OHT 患者中,参与脂肪酸生物合成和酮体代谢的独特代谢物上调,而犬尿氨酸途径的代谢物下调。代谢途径的不同影响可能解释了为什么OHT患者最初不会出现视神经退化或视神经退化的恢复能力更强。NTG和OHT患者的代谢组调节方式与对照组不同,并显示出对能量产生很重要的代谢物的失调。这些失调过程可能会导致眼压升高,并最终导致 RGC 细胞死亡。
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来源期刊
International Journal of Molecular Sciences
International Journal of Molecular Sciences Chemistry-Organic Chemistry
CiteScore
8.10
自引率
10.70%
发文量
13472
审稿时长
17.49 days
期刊介绍: The International Journal of Molecular Sciences (ISSN 1422-0067) provides an advanced forum for chemistry, molecular physics (chemical physics and physical chemistry) and molecular biology. It publishes research articles, reviews, communications and short notes. Our aim is to encourage scientists to publish their theoretical and experimental results in as much detail as possible. Therefore, there is no restriction on the length of the papers or the number of electronics supplementary files. For articles with computational results, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material (including animated pictures, videos, interactive Excel sheets, software executables and others).
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