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HIF-1α is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium

  1. David Wu
  2. Ru-Ting Huang
  3. Robert B Hamanaka
  4. Matthew D Krause
  5. Myung-Jin Oh
  6. Cheng-Hsiang Kuo
  7. Recep Nigdelioglu
  8. Angelo Y Meliton
  9. Leah Witt
  10. Guohao Dai
  11. Mete Civelek
  12. Nanduri R Prabhakar
  13. Yun Fang  Is a corresponding author
  14. Gökhan M Mutlu  Is a corresponding author
  1. The University of Chicago, United States
  2. Northeastern University, United States
  3. University of Virginia, United States
Research Article
  • Cited 20
  • Views 1,790
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Cite this article as: eLife 2017;6:e25217 doi: 10.7554/eLife.25217

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.

Article and author information

Author details

  1. David Wu

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3162-3238
  2. Ru-Ting Huang

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Robert B Hamanaka

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8909-356X
  4. Matthew D Krause

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Myung-Jin Oh

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Cheng-Hsiang Kuo

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4885-9020
  7. Recep Nigdelioglu

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Angelo Y Meliton

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Leah Witt

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Guohao Dai

    Department of Bioengineering, Northeastern University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Mete Civelek

    Department of Biomedical Engineering, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Nanduri R Prabhakar

    Institute for Integrative Physiology, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Yun Fang

    Department of Medicine, The University of Chicago, Chicago, United States
    For correspondence
    yfang1@medicine.bsd.uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
  14. Gökhan M Mutlu

    Department of Medicine, The University of Chicago, Chicago, United States
    For correspondence
    gmutlu@medicine.bsd.uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2056-612X

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).

Reviewing Editor

  1. Kari Alitalo, University of Helsinki, Finland

Publication history

  1. Received: January 17, 2017
  2. Accepted: May 26, 2017
  3. Accepted Manuscript published: May 30, 2017 (version 1)
  4. Version of Record published: July 3, 2017 (version 2)

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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