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.

Plasma stem cell factor levels are associated with risk of cardiovascular disease and death

“…The present observation that low circulating levels of SCF are also associated with an increased cardiovascular mortality adds further support to this notion. Recent studies performed in Apoe-/mice have shown that inhibition of glucose uptake in hematopoietic SC is associated with decreased proliferation of these cells as well as with accelerated atherosclerosis [47]. However, it should be noted that SCF also may have adverse effects on plaque stability through activation of mast cell.…”

Diabetes propels the risk for cardiovascular disease: sweet monocytes becoming aggressive?

“…Nevertheless, reducing glycolysis corrects the proinflammatory phenotype of macrophages derived from patients with atherosclerotic coronary artery disease [52]. In addition, a reduction in glycolysis in myeloid cells via GLUT1 deletion inhibits expansion and proliferation of myeloid progenitor cells, leading to a reduction of plaque macrophages in an animal model for atherosclerosis in vivo [73]. …”

2014 Jeffrey M. Hoeg Award Lecture

“…These investigators found that the increase in myelopoiesis in diabetic mice was due to increased expression of S100A8/S100A9, which induced GMP proliferation through interaction with the receptor for advanced glycation endproducts (RAGE). Interestingly, Sarrazy et al recently showed that changes in intracellular glucose metabolism in CMPs increased CMP proliferation and monocyte and neutrophil production, and this was regulated by expression of the glucose transporter type 1 (Glut1) 53 . Such data suggest that factors that change metabolism of bone marrow progenitors, such as those linked to hyperlipidemia and hyperglycemia, are key regulators of myelopoiesis.…”