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
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.).
Circ Res. 2016 Apr 1;118(7):1062-77. doi: 10.1161/CIRCRESAHA.115.307599. Epub 2016 Feb 29.
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.
Here, we directly investigated the role of Glut1-mediated glucose uptake in apolipoprotein E-deficient (ApoE(-/-)) mouse model of atherosclerosis.
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.
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.
炎症性动脉粥样硬化斑块可通过使用葡萄糖类似物（18）F-氟脱氧葡萄糖的非侵入性正电子发射断层扫描和计算机断层扫描成像来可视化，但其潜在机制尚不清楚。
在此，我们直接研究了葡萄糖转运蛋白1（Glut1）介导的葡萄糖摄取在载脂蛋白E缺陷（ApoE（-/-））动脉粥样硬化小鼠模型中的作用。
我们首先表明，ApoE（-/-）小鼠动脉粥样硬化斑块中糖酵解通量的增强与造血干细胞和多能祖细胞的代谢活性增强以及这些细胞中更高的Glut1表达有关。从机制上讲，ApoE（-/-）造血干细胞和多能祖细胞中Glut1的调节并非由于缺氧诱导因子1α信号的改变或骨髓的氧合状态，而是粒细胞-巨噬细胞集落刺激因子/白细胞介素-3受体共同β亚基激活的结果，该激活驱动线粒体对糖酵解底物的利用。通过将野生型、Glut1（+/-）、ApoE（-/-）和ApoE（-/-）Glut1（+/-）小鼠的骨髓移植到高胆固醇血症的ApoE缺陷小鼠中，我们发现Glut1缺陷逆转了ApoE（-/-）造血干细胞和多能祖细胞的增殖和扩增，这阻止了ApoE（-/-）小鼠移植ApoE（-/-）骨髓后的骨髓生成并加速了动脉粥样硬化，并导致这些小鼠脾脏和主动脉弓中的葡萄糖摄取减少。
我们发现Glut1通过调节造血干细胞和多能祖细胞的维持以及骨髓单核细胞命运，将ApoE（-/-）小鼠动脉粥样硬化斑块中增强的葡萄糖摄取与其骨髓生成联系起来，并表明Glut1是动脉粥样硬化的潜在药物靶点。
