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Circ Res. 2016 Apr 1;118(7):1062-77. doi: 10.1161/CIRCRESAHA.115.307599. Epub 2016 Feb 29.

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

Author information

1
From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.).
2
From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.). laurent.yvancharvet@unice.fr.

Abstract

RATIONALE:

Inflamed atherosclerotic plaques can be visualized by noninvasive positron emission and computed tomographic imaging with (18)F-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.

KEYWORDS:

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

PMID:
26926469
PMCID:
PMC4824305
DOI:
10.1161/CIRCRESAHA.115.307599
[Indexed for MEDLINE]
Free PMC Article

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