Abstract
BackgroundDiabetes 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.MethodsLow-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−/−ApoB100/100 and LDLR−/−ApoB100/100) were studied. Distribution kinetics of choline analogue 18F-fluoromethylcholine (18F-FMCH) was assessed in vivo by positron emission tomography (PET) imaging. Then, aortic uptakes of 18F-FMCH and glucose analogue 18F-fluorodeoxyglucose (18F-FDG), were assessed ex vivo by gamma counting and autoradiography of tissue sections. The 18F-FMCH uptake in atherosclerotic plaques was further compared with macrophage infiltration and the plasma levels of cytokines and metabolic markers.ResultsThe 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 18F-FMCH was rapid. Both the absolute 18F-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 18F-FMCH uptake co-localized with macrophage-rich atherosclerotic plaques. 18F-FMCH uptake in plaques correlated with levels of total cholesterol, insulin, C-peptide and leptin. In comparison with 18F-FDG, 18F-FMCH provided similar or higher plaque-to-background ratios in diabetic mice.ConclusionsType 2 diabetes enhances the uptake of choline that reflects inflammation in atherosclerotic plaques in mice. PET tracer 18F-FMCH is a potential tool to study vascular inflammation associated with diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0340-6) contains supplementary material, which is available to authorized users.
Highlights
Diabetes is a risk factor for atherosclerosis associated with oxidative stress, inflammation and cell proliferation
Diabetes is associated with an increased risk of atherosclerotic cardiovascular disease (CVD), and it is common in patients with known or at risk of CVD [1]
Correlation of 18F‐FMCH plaque uptake and plasma biomarkers Plasma samples from eleven LDLR−/−ApoB100/100, eleven insulin-like growth factor II (IGF-II)/LDLR−/−ApoB100/100 and nine C57BL/6N mice were analyzed for lipids and lipid-associated proteins, metabolic markers, and inflammatory mediators
Summary
Diabetes is a risk factor for atherosclerosis associated with oxidative stress, inflammation and cell proliferation. Various factors, including increased oxidative stress and subsequent activation of pro-inflammatory pathways, as well as increased cell proliferation in the arterial wall, contribute to accelerated atherosclerosis in diabetes [2]. Accumulation of 18F-FDG in atherosclerotic plaques has been attributed to high glucose uptake in macrophages [4, 10]. High blood glucose levels in T2DM can diminish 18F-FDG uptake in atherosclerosis [7]. These factors may complicate the interpretation of 18F-FDG signal from arteries, especially in diabetic individuals, and alternative tracers for the quantification of inflammation in atherosclerosis have been investigated [15,16,17]
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