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

Description

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.

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