Journal article
13C Metabolic Flux Analysis Indicates Endothelial Cells Attenuate Metabolic Perturbations by Modulating TCA Activity
METABOLITES, v 11(4), 226
Apr 2021
PMID: 33917224
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Disrupted endothelial metabolism is linked to endothelial dysfunction and cardiovascular disease. Targeted metabolic inhibitors are potential therapeutics; however, their systemic impact on endothelial metabolism remains unknown. In this study, we combined stable isotope labeling with C-13 metabolic flux analysis (C-13 MFA) to determine how targeted inhibition of the polyol (fidarestat), pentose phosphate (DHEA), and hexosamine biosynthetic (azaserine) pathways alters endothelial metabolism. Glucose, glutamine, and a four-carbon input to the malate shuttle were important carbon sources in the baseline human umbilical vein endothelial cell (HUVEC) C-13 MFA model. We observed two to three times higher glutamine uptake in fidarestat and azaserine-treated cells. Fidarestat and DHEA-treated HUVEC showed decreased C-13 enrichment of glycolytic and TCA metabolites and amino acids. Azaserine-treated HUVEC primarily showed C-13 enrichment differences in UDP-GlcNAc. C-13 MFA estimated decreased pentose phosphate pathway flux and increased TCA activity with reversed malate shuttle direction in fidarestat and DHEA-treated HUVEC. In contrast, C-13 MFA estimated increases in both pentose phosphate pathway and TCA activity in azaserine-treated cells. These data show the potential importance of endothelial malate shuttle activity and suggest that inhibiting glycolytic side branch pathways can change the metabolic network, highlighting the need to study systemic metabolic therapeutic effects.
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Details
- Title
- 13C Metabolic Flux Analysis Indicates Endothelial Cells Attenuate Metabolic Perturbations by Modulating TCA Activity
- Publication Details
- METABOLITES, v 11(4), 226
- Publisher
- MDPI; BASEL
- Grant note
- This research was funded by NIH 1R01HL140239 to AC and NSF DGE-1632976 to BM.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:000643271700001
- Scopus ID
- 2-s2.0-85104295601
- Other Identifier
- 991021860752104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology