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 journalArticlepeer-review

33 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

All Science Journal Classification (ASJC) codes

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

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