期刊
CIRCULATION RESEARCH
卷 118, 期 7, 页码 1062-1077出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.115.307599
关键词
glucose transporter type 1; cholesterol; myeloid cells; atherosclerosis; glycolysis; bone marrow
资金
- INSERM ATIP-AVENIR
- Fondation de France [201300038585]
- Agence Nationale de la Recherche (ANR)
Rationale: Inflamed atherosclerotic plaques can be visualized by noninvasive positron emission and computed tomographic imaging with F-18-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 1 alpha signaling or the oxygenation status of the bone marrow but was the consequence of the activation of the common beta 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.
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