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

David Wu, Ru Ting Huang, Robert B. Hamanaka, Matt Krause, Myung Jin Oh, Cheng-Hsiang Kuo, Recep Nigdelioglu, Angelo Y. Meliton, Leah Witt, Guohao Dai, Mete Civelek, Nanduri R. Prabhakar, Yun Fang, Gökhan M. Mutlu

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Article numbere25217
JournaleLife
Volume6
DOIs
Publication statusPublished - 2017 May 30

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Hypoxia-Inducible Factor 1
Endothelial cells
Vascular Endothelium
Swine
Endothelial Cells
Glycolysis
Inflammation
Blood Vessels
Reactive Oxygen Species
Chemical activation
NADPH Oxidase
Hemodynamics
Arches
Enzymes
Thoracic Aorta
Metabolism
Energy Metabolism
Endothelium
Atherosclerosis

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Wu, David ; Huang, Ru Ting ; Hamanaka, Robert B. ; Krause, Matt ; Oh, Myung Jin ; Kuo, Cheng-Hsiang ; Nigdelioglu, Recep ; Meliton, Angelo Y. ; Witt, Leah ; Dai, Guohao ; Civelek, Mete ; Prabhakar, Nanduri R. ; Fang, Yun ; Mutlu, Gökhan M. / HIF-1α is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium. In: eLife. 2017 ; Vol. 6.
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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.",
author = "David Wu and Huang, {Ru Ting} and Hamanaka, {Robert B.} and Matt Krause and Oh, {Myung Jin} and Cheng-Hsiang Kuo and Recep Nigdelioglu and Meliton, {Angelo Y.} and Leah Witt and Guohao Dai and Mete Civelek and Prabhakar, {Nanduri R.} and Yun Fang and Mutlu, {G{\"o}khan M.}",
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Wu, D, Huang, RT, Hamanaka, RB, Krause, M, Oh, MJ, Kuo, C-H, Nigdelioglu, R, Meliton, AY, Witt, L, Dai, G, Civelek, M, Prabhakar, NR, Fang, Y & Mutlu, GM 2017, 'HIF-1α is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium', eLife, vol. 6, e25217. https://doi.org/10.7554/eLife.25217

HIF-1α is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium. / Wu, David; Huang, Ru Ting; Hamanaka, Robert B.; Krause, Matt; Oh, Myung Jin; Kuo, Cheng-Hsiang; Nigdelioglu, Recep; Meliton, Angelo Y.; Witt, Leah; Dai, Guohao; Civelek, Mete; Prabhakar, Nanduri R.; Fang, Yun; Mutlu, Gökhan M.

In: eLife, Vol. 6, e25217, 30.05.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HIF-1α is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium

AU - Wu, David

AU - Huang, Ru Ting

AU - Hamanaka, Robert B.

AU - Krause, Matt

AU - Oh, Myung Jin

AU - Kuo, Cheng-Hsiang

AU - Nigdelioglu, Recep

AU - Meliton, Angelo Y.

AU - Witt, Leah

AU - Dai, Guohao

AU - Civelek, Mete

AU - Prabhakar, Nanduri R.

AU - Fang, Yun

AU - Mutlu, Gökhan M.

PY - 2017/5/30

Y1 - 2017/5/30

N2 - 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.

AB - 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.

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U2 - 10.7554/eLife.25217

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