Published May 30, 2017
| Version v1
Journal article
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HIF-1α is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium
Creators
- 1. University of Chicago
- 2. Northeastern University
- 3. University of Virginia
Description
Hemodynamic forces regulate vascular functions. Disturbed flow (DF) occurs in arterial bifurcations and curvatures, activates endothelial cells (ECs), and results in vascular inflammation and ultimately atherosclerosis. However, how DF alters EC metabolism, and whether resulting metabolic changes induce EC activation, is unknown. Using transcriptomics and bioenergetic analysis, we discovered that DF induces glycolysis and reduces mitochondrial respiratory capacity in human aortic ECs. DF-induced metabolic reprogramming required hypoxia inducible factor-1α (HIF-1α), downstream of NAD(P)H oxidase-4 (NOX4)-derived reactive oxygen species (ROS). HIF-1α increased glycolytic enzymes and pyruvate dehydrogenase kinase-1 (PDK-1), which reduces mitochondrial respiratory capacity. Swine aortic arch endothelia exhibited elevated ROS, NOX4, HIF-1α, and glycolytic enzyme and PDK1 expression, suggesting that DF leads to metabolic reprogramming in vivo. Inhibition of glycolysis reduced inflammation suggesting a causal relationship between flow-induced metabolic changes and EC activation. These findings highlight a previously uncharacterized role for flow-induced metabolic reprogramming and inflammation in ECs.
Data availability
The following data sets were generated:
Wu D Huang R-T Hamanaka RB Krause MD Kuo C-H Nigdelioglu R Meliton AY Witt L Dai G Civelek M Prabhakar NR Fang Y Mutlu GM (2017) Flow transcriptome of human aortic endothelial cells Publicly available at Zenodo.org under a Creative Commons Attribution 4.0 License. https://doi.org/10.5281/zenodo.260122
Wu D Huang R-T Hamanaka RB Krause MD Kuo C-H Nigdelioglu R Meliton AY Witt L Dai G Civelek M Prabhakar NR Fang Y Mutlu GM (2017) HIF-1α knockdown under disturbed flow in human aortic endothelial cells Publicly available at Zenodo.org under a Creative Commons Attribution 4.0 License. https://doi.org/10.5281/zenodo.260120
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Additional details
Identifiers
- DOI
- 10.7554/eLife.25217
- Other
- oai:uchicago.tind.io:9906
Funding
- National Institutes of Health
- T32HL007605
- American Heart Association
- 15POST255900003
- National Institutes of Health
- F32HL134288
- National Institutes of Health
- R21ES025644
- National Institutes of Health
- K01AR066579
- National Institutes of Health
- R01ES015024
- National Institutes of Health
- P01HL090554
- National Institutes of Health
- R00HL103789
- American Heart Association
- BGIA7080012