Plasma Metabolomics Profiles Associated with Endothelial Health and Dysfunction and their Influence on Endothelial Metabolism
Óttar Rolfsson (1), Sarah McGarrity (1), Hanne Hee Henrikssen (2), Per Johansson (2) (1) University of Iceland, Reykjavik Iceland (2) Rigshospitalet, Copenhagen, Denmark
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Óttar Rolfsson (Presenter) University of Iceland
Presenter Bio: I am a trained biochemist and structural biologist who has spent the last decade analyzing cellular metabolism by UPLC-MS and building quantitative models of cardiovascular cell metabolism using genome scale modelling techniques.
Relevant Financial Disclosures
(within past 24 months)
No relevant financial relationship(s) to disclose.
Abstract
Background: Endothelial dysfunction (ED) contributes to diseases of the vasculature by influencing blood pressure, clotting and transport of fluids, nutrients and immune cells. Metabolic phenotypes associated with ED are not well characterized due to difficulties in assessing endothelial metabolism in situ.
Methods: We built a cell scale metabolic network model of endothelial metabolism (iEC2812) and applied it to infer endothelial metabotypes from i) plasma metabolomics data from 20 trauma patients vs. 20 controls and ii) ASGR1del12 carriers vs. controls to identify reactions associated with both dysfunctional and above normally healthy endothelium, respectively. Proposed changes in endothelial metabolism in situ were validated in endothelial cell models in vitro by metabolomics analysis of spent media and intracellular 13C glucose and 15N glutamine isotopologue analysis.
Results: Network analysis of plasma metabolomics data suggested that endothelial glycocalyx maintenance may contribute to endothelial dysfunction via altered flux into the hexosamine biosynthetic pathway. HUVEC monolayers titrated with physiological concentrations of catecholamines to induce endothelial dysfunction resulted in increased permeability and glycocalyx loss as verified by TEM, immunostaining and by permeability assays. A drop in the intracellular concentrations of the glycan precursors UDP-glucose and N-acetyl-glucosamine was observed. Isotopologue analysis supported lower turnover of glycocalyx intermediates and lower glycolytic and TCA cycle flux in dysfunctional endothelial cells.
Conclusion: Metabolic network analysis of three independent plasma metabolomics datasets highlighted the importance of glycan synthesis to endothelial health. Induction of endothelial dysfunction in vitro is accompanied by compromised glycan synthesis.
= Discovery stage.
= Translation stage.
= Clinically available.
