Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE -/- Mice

Vincent Sarrazy, Manon Viaud, Marit Westerterp, Stoyan Ivanov, Sophie Giorgetti-Peraldi, Rodolphe Guinamard, Emmanuel L. Gautier, Edward B. Thorp, Darryl C. De Vivo, Laurent Yvan-Charvet*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Rationale: Inflamed atherosclerotic plaques can be visualized by noninvasive positron emission and computed tomographic imaging with 18F-fluorodeoxyglucose, a glucose analog, but the underlying mechanisms are poorly understood. Objective: Here, we directly investigated the role of Glut1-mediated glucose uptake in apolipoprotein E-deficient (ApoE-/-) mouse model of atherosclerosis. Methods and Results: We first showed that the enhanced glycolytic flux in atheromatous plaques of ApoE-/- mice was associated with the enhanced metabolic activity of hematopoietic stem and multipotential progenitor cells and higher Glut1 expression in these cells. Mechanistically, the regulation of Glut1 in ApoE-/- hematopoietic stem and multipotential progenitor cells was not because of alterations in hypoxia-inducible factor 1α signaling or the oxygenation status of the bone marrow but was the consequence of the activation of the common β subunit of the granulocyte-macrophage colony-stimulating factor/interleukin-3 receptor driving glycolytic substrate utilization by mitochondria. By transplanting bone marrow from WT, Glut1+/-, ApoE-/-, and ApoE-/-Glut1+/- mice into hypercholesterolemic ApoE-deficient mice, we found that Glut1 deficiency reversed ApoE-/- hematopoietic stem and multipotential progenitor cell proliferation and expansion, which prevented the myelopoiesis and accelerated atherosclerosis of ApoE-/- mice transplanted with ApoE-/- bone marrow and resulted in reduced glucose uptake in the spleen and aortic arch of these mice. Conclusions: We identified that Glut1 connects the enhanced glucose uptake in atheromatous plaques of ApoE-/- mice with their myelopoiesis through regulation of hematopoietic stem and multipotential progenitor cell maintenance and myelomonocytic fate and suggests Glut1 as potential drug target for atherosclerosis.

Original languageEnglish (US)
Pages (from-to)1062-1077
Number of pages16
JournalCirculation research
Volume118
Issue number7
DOIs
StatePublished - Apr 1 2016

Keywords

  • atherosclerosis
  • bone marrow
  • cholesterol
  • glucose transporter type 1
  • glycolysis
  • myeloid cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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