Modelling the Metabolism of Human Endothelial Dysfunction

Modelling the metabolism of human endothelial dysfunction.

Sarah McGarrity¹, Haraldur Halldórsson², Sirus Palsson⁴, Pär Johansson³, and Ottar Rolfsson¹.

1. Center for Systems Biology, University of Iceland, Reykjavik, Iceland.

2. Department of Pharmacology and Toxicology, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

3. Section for Transfusion Medicine, Capital Region Blood Bank, Copenhagen University Hospital, Rigshospitalet, Denmark.

4. Sinopia Biosciences Inc, San Diego, California, USA.

Endothelial dysfunction is associated with multiple pathological conditions. Endothelial cells form the lining of blood vessels and perform many important functions that when offset can contribute to chronic conditions such as atherosclerosis and diabetes, and acute conditions such as sepsis. The links between endothelial cell permeability and metabolism have recently been highlighted (Patella, Schug et al. 2015). The metabolic state of healthy endothelium and how metabolism impacts endothelial function, however, remains incompletely defined. To address this, we report the construction of a genome scale metabolic model (GEM) of human umbilical vein endothelial cells (HUVEC), a well-studied cell culture model used extensively to investigate endothelial cell functions.

Using the COBRA toolbox in Matlab (Schellenberger, Que et al. 2011), Recon 1(Duarte, Becker et al. 2007) was constrained to include reactions specific to HUVECs using publically available transcriptomic and proteomic studies. The HUVEC GEM captures core metabolic phenotypes based on these data sets. Model curation is however currently ongoing. Gaps relevant to HUVEC metabolism are addressed by adding reactions from Recon 2 (Thiele, Swainston et al. 2013) supported by relevant bibliomic data. To further constrain the model inhouse exo-metablomic data descriptive of HUVECs growth will be used to further constrain baseline metabolite flux phenotypes.

Investigation of endothelial cell metabolism will help to better understand endothelial cell functions. The literature-based, context-specific model of HUVEC cell metabolism described here will ultimately serve as a tool for the interpretation of omics data allowing correlation of global metabolic phenotypes with biomarkers of endothelial dysfunction including soluble Thrombomodulin and Syndecan-1.

Duarte, N., et al. (2007). "Global reconstruction of the human metabolic network based on genomic and bibliomic data." PNAS 104(6): 1777-1782.

Patella, F., et al. (2015). "Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability." Molecular & Cellular Proteomics 14(3): 621-634.

Schellenberger, J., et al. (2011). "Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0." Nature Protocols 6(9): 1290-1307.

Thiele, I., et al. (2013). "A community-driven global reconstruction of human metabolism." Nature Biotechnology 31(5): 419-425.