HIF-1α is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium
- The University of Chicago, United States
- Northeastern University, United States
- University of Virginia, United States
Abstract
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
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Flow transcriptome of human aortic endothelial cellsPublicly available at Zenodo.org under a Creative Commons Attribution 4.0 License.
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HIF-1α knockdown under disturbed flow in human aortic endothelial cellsPublicly available at Zenodo.org under a Creative Commons Attribution 4.0 License.
Article and author information
Author details
Funding
National Institutes of Health (T32HL007605)
- David Wu
- Myung-Jin Oh
American Heart Association (15POST255900003)
- Recep Nigdelioglu
National Institutes of Health (F32HL134288)
- David Wu
National Institutes of Health (R21ES025644)
- Gökhan M Mutlu
National Institutes of Health (K01AR066579)
- Robert B Hamanaka
National Institutes of Health (R01ES015024)
- Gökhan M Mutlu
National Institutes of Health (P01HL090554)
- Nanduri R Prabhakar
National Institutes of Health (R00HL103789)
- Yun Fang
American Heart Association (BGIA7080012)
- Yun Fang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures were in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The use of vertebrate animal tissues was approved by the Animal Care and Use Committee of the University of Chicago (Permit # 72281). The use of vertebrate animal tissues obtained from outside the University of Chicago was approved by the Animal Care and Use Committee of the University of Chicago (Permit # 72500).
Copyright
© 2017, Wu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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