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

Abstract
Rationale: Inflamed atherosclerotic plaques can be visualized by non-invasive PET-CT imaging with 18FDG, a glucose analog but the underlying mechanisms are poorly understood.
Objective: Here, we directly investigated the role of Glut1-mediated glucose uptake in ApoE-/- mouse model of atherosclerosis.
Methods and Results: We first show that the enhanced glycolytic flux in atheromatous plaques of ApoE-/- mice was associated with the enhanced metabolic activity of hematopoietic stem and multi-potential progenitors (HSPCs) and higher Glut1 expression in these cells. Mechanistically, the regulation of Glut1 in ApoE-/- HSPCs was not due to alterations in hypoxia-inducible factor 1α (HIF1α) 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 BM from WT, Glut1+/-, ApoE-/- and ApoE-/-Glut1+/- mice into hypercholesterolemic ApoE deficient mice, we found that Glut1 deficiency reversed ApoE-/- HSPC proliferation and expansion, which prevented the myelopoiesis and accelerated atherosclerosis of ApoE-/- mice transplanted with ApoE-/- BM 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 HSPC maintenance and myelomonocytic fate and suggest Glut1 as potential drug target for atherosclerosis.
- cell cycling
- myeloid commitment
- Glut1
- atherosclerosis
- bone marrow
- cholesterol
- hematopoietic stem cells
- glucose glycolysis
- Received September 10, 2015.
- Revision received February 25, 2016.
- Accepted February 26, 2016.
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- Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE-/- MiceVincent Sarrazy, Manon Viaud, Marit Westerterp, Stoyan Ivanov, Sophie Giorgetti-Peraldi, Rodolphe Guinamard, Emmanuel L Gautier, Edward B Thorp, Darryl C De Vivo and Laurent Yvan-CharvetCirculation Research. 2016;CIRCRESAHA.115.307599, originally published February 29, 2016https://doi.org/10.1161/CIRCRESAHA.115.307599
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- Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE-/- MiceVincent Sarrazy, Manon Viaud, Marit Westerterp, Stoyan Ivanov, Sophie Giorgetti-Peraldi, Rodolphe Guinamard, Emmanuel L Gautier, Edward B Thorp, Darryl C De Vivo and Laurent Yvan-CharvetCirculation Research. 2016;CIRCRESAHA.115.307599, originally published February 29, 2016https://doi.org/10.1161/CIRCRESAHA.115.307599