Tavakoli Sina, Downs Kevin, Short John D, Nguyen Huynh Nga, Lai Yanlai, Jerabek Paul A, Goins Beth, Toczek Jakub, Sadeghi Mehran M, Asmis Reto
From the Department of Radiology (S.T.) and Department of Medicine (S.T.), University of Pittsburgh, PA; Department of Cellular and Structural Biology (K.D), Department of Pharmacology (J.D.S.), Department of Biochemistry (H.N.N., R.A.), Department of Clinical Laboratory Sciences (Y.L., R.A.), Department of Radiology (P.A.J., B.G., R.A.), and Research Imaging Institute (P.A.J.), University of Texas Health Science Center at San Antonio; and Section of Cardiovascular Medicine (J.T., M.M.S.) and Cardiovascular Research Center (J.T., M.M.S.), Yale School of Medicine, New Haven, CT.
Arterioscler Thromb Vasc Biol. 2017 Oct;37(10):1840-1848. doi: 10.1161/ATVBAHA.117.308848. Epub 2017 Aug 10.
Despite the early promising results of F-fluorodeoxyglucose positron emission tomography for assessment of vessel wall inflammation, its accuracy in prospective identification of vulnerable plaques has remained limited. Additionally, previous studies have indicated that F-fluorodeoxyglucose uptake alone may not allow for accurate identification of specific macrophage activation states. We aimed to determine whether combined measurement of glucose and glutamine accumulation-the 2 most important bioenergetic substrates for macrophages-improves the distinction of macrophage inflammatory states and can be utilized to image atherosclerosis.
Murine peritoneal macrophages (MΦ) were activated ex vivo into proinflammatory states with either lipopolysaccharide (MΦ) or interferon-γ+tumor necrosis factor-α (MΦ). An alternative polarization phenotype was induced with interleukin-4 (MΦ). The pronounced increase in 2-deoxyglucose uptake distinguishes MΦ from MΦ, MΦ, and unstimulated macrophages (MΦ). Despite having comparable levels of 2-deoxyglucose accumulation, MΦ can be distinguished from both MΦ and MΦ based on the enhanced glutamine accumulation, which was associated with increased expression of a glutamine transporter, . Ex vivo autoradiography experiments demonstrated distinct and heterogenous patterns of F-fluorodeoxyglucose and C-glutamine accumulation in atherosclerotic lesions of low-density lipoprotein receptor-null mice fed a high-fat diet.
Combined assessment of glutamine and 2-deoxyglucose accumulation improves the ex vivo identification of macrophage activation states. Combined ex vivo metabolic imaging demonstrates heterogenous and distinct patterns of substrate accumulation in atherosclerotic lesions. Further studies are required to define the in vivo significance of glutamine uptake in atherosclerosis and its potential application in identification of vulnerable plaques.
尽管F-氟脱氧葡萄糖正电子发射断层扫描在评估血管壁炎症方面早期取得了令人鼓舞的结果，但其在前瞻性识别易损斑块方面的准确性仍然有限。此外，先前的研究表明，仅F-氟脱氧葡萄糖摄取可能无法准确识别特定的巨噬细胞激活状态。我们旨在确定联合测量葡萄糖和谷氨酰胺积累（巨噬细胞的两种最重要的生物能量底物）是否能改善对巨噬细胞炎症状态的区分，并可用于动脉粥样硬化成像。
将小鼠腹腔巨噬细胞（MΦ）在体外分别用脂多糖（MΦ）或干扰素-γ + 肿瘤坏死因子-α（MΦ）激活为促炎状态。用白细胞介素-4诱导另一种极化表型（MΦ）。2-脱氧葡萄糖摄取的显著增加将MΦ与MΦ、MΦ和未刺激的巨噬细胞（MΦ）区分开来。尽管2-脱氧葡萄糖积累水平相当，但基于增强的谷氨酰胺积累，MΦ可与MΦ和MΦ区分开来，这与谷氨酰胺转运体的表达增加有关。体外放射自显影实验表明，在喂食高脂饮食的低密度脂蛋白受体缺失小鼠的动脉粥样硬化病变中，F-氟脱氧葡萄糖和C-谷氨酰胺积累呈现出不同且异质的模式。
联合评估谷氨酰胺和2-脱氧葡萄糖积累可改善体外对巨噬细胞激活状态的识别。联合体外代谢成像显示动脉粥样硬化病变中底物积累的异质和不同模式。需要进一步研究来确定谷氨酰胺摄取在动脉粥样硬化中的体内意义及其在识别易损斑块中的潜在应用。
