Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE−/− Mice. Issue 7 (1st April 2016)

• Record Type: Journal Article
• Authors: Sarrazy, Vincent; Viaud, Manon; Westerterp, Marit; Ivanov, Stoyan; Giorgetti-Peraldi, Sophie; Guinamard, Rodolphe; Gautier, Emmanuel L.; Thorp, Edward B.; De Vivo, Darryl C.; Yvan-Charvet, Laurent
• Is Part Of: Circulation research. Volume 118:Issue 7(2016)
• Publication Date: 2016-04-01
• Subjects: atherosclerosis -- bone marrow -- cholesterol -- glucose transporter type 1 -- glycolysis -- myeloid cells; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.115.307599
• Languages: English
• ISSNs: 0009-7330

Abstract

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. Abstract : Supplemental Digital Content is available in the text.