Hellberg Sanna, Silvola Johanna M U, Kiugel Max, Liljenbäck Heidi, Metsälä Olli, Viljanen Tapio, Metso Jari, Jauhiainen Matti, Saukko Pekka, Nuutila Pirjo, Ylä-Herttuala Seppo, Knuuti Juhani, Roivainen Anne, Saraste Antti
Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, 20520, Turku, Finland.
Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland.
Cardiovasc Diabetol. 2016 Feb 6;15:26. doi: 10.1186/s12933-016-0340-6.
Diabetes is a risk factor for atherosclerosis associated with oxidative stress, inflammation and cell proliferation. The purpose of this study was to evaluate arterial choline uptake and its relationship to atherosclerotic inflammation in diabetic and non-diabetic hypercholesterolemic mice.
Low-density lipoprotein-receptor deficient mice expressing only apolipoprotein B100, with or without type 2 diabetes caused by pancreatic overexpression of insulin-like growth factor II (IGF-II/LDLR(-/-)ApoB(100/100) and LDLR(-/-)ApoB(100/100)) were studied. Distribution kinetics of choline analogue (18)F-fluoromethylcholine ((18)F-FMCH) was assessed in vivo by positron emission tomography (PET) imaging. Then, aortic uptakes of (18)F-FMCH and glucose analogue (18)F-fluorodeoxyglucose ((18)F-FDG), were assessed ex vivo by gamma counting and autoradiography of tissue sections. The (18)F-FMCH uptake in atherosclerotic plaques was further compared with macrophage infiltration and the plasma levels of cytokines and metabolic markers.
The aortas of all hypercholesterolemic mice showed large, macrophage-rich atherosclerotic plaques. The plaque burden and densities of macrophage subtypes were similar in diabetic and non-diabetic animals. The blood clearance of (18)F-FMCH was rapid. Both the absolute (18)F-FMCH uptake in the aorta and the aorta-to-blood uptake ratio were higher in diabetic than in non-diabetic mice. In autoradiography, the highest (18)F-FMCH uptake co-localized with macrophage-rich atherosclerotic plaques. (18)F-FMCH uptake in plaques correlated with levels of total cholesterol, insulin, C-peptide and leptin. In comparison with (18)F-FDG, (18)F-FMCH provided similar or higher plaque-to-background ratios in diabetic mice.
Type 2 diabetes enhances the uptake of choline that reflects inflammation in atherosclerotic plaques in mice. PET tracer (18)F-FMCH is a potential tool to study vascular inflammation associated with diabetes.
糖尿病是动脉粥样硬化的一个危险因素，与氧化应激、炎症和细胞增殖相关。本研究的目的是评估糖尿病和非糖尿病高胆固醇血症小鼠的动脉胆碱摄取及其与动脉粥样硬化炎症的关系。
研究了仅表达载脂蛋白B100的低密度脂蛋白受体缺陷小鼠，这些小鼠有或没有因胰腺过表达胰岛素样生长因子II（IGF-II/LDLR(-/-)ApoB(100/100)和LDLR(-/-)ApoB(100/100)）导致的2型糖尿病。通过正电子发射断层扫描（PET）成像在体内评估胆碱类似物（18）F-氟甲基胆碱（（18）F-FMCH）的分布动力学。然后，通过γ计数和组织切片的放射自显影在体外评估（18）F-FMCH和葡萄糖类似物（18）F-氟脱氧葡萄糖（（18）F-FDG）的主动脉摄取。将动脉粥样硬化斑块中的（18）F-FMCH摄取与巨噬细胞浸润以及细胞因子和代谢标志物的血浆水平进一步进行比较。
所有高胆固醇血症小鼠的主动脉均显示出大的、富含巨噬细胞的动脉粥样硬化斑块。糖尿病和非糖尿病动物的斑块负担和巨噬细胞亚型密度相似。（18）F-FMCH的血液清除迅速。糖尿病小鼠主动脉中（18）F-FMCH的绝对摄取量和主动脉与血液的摄取比均高于非糖尿病小鼠。在放射自显影中，最高的（18）F-FMCH摄取与富含巨噬细胞的动脉粥样硬化斑块共定位。斑块中（18）F-FMCH摄取与总胆固醇、胰岛素、C肽和瘦素水平相关。与（18）F-FDG相比，（18）F-FMCH在糖尿病小鼠中提供了相似或更高的斑块与背景比值。
2型糖尿病增强了胆碱的摄取，这反映了小鼠动脉粥样硬化斑块中的炎症。PET示踪剂（18）F-FMCH是研究与糖尿病相关的血管炎症的潜在工具。
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