Type 2 diabetes enhances arterial uptake of choline in atherosclerotic mice: an imaging study with positron emission tomography tracer 18F-fluoromethylcholine

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.

New methods to image unstable atherosclerotic plaques

“…Increased choline uptake has been shown in tumor cells and activated macrophages [ 84 ]. Its potential for human atherosclerotic imaging was confirmed by ex vivo and in vivo mouse model studies of atherosclerosis where uptake was significantly higher in atherosclerotic versus healthy aorta [ 85 – 87 ]. A strong association between large vessel uptake and atherosclerotic changes in the arterial wall has been demonstrated in a cohort of prostate cancer patients with an apparent inverse relationship with calcification [ 88 ].…”

Positron Emission Tomography Imaging of Macrophages in Atherosclerosis with 18F-GE-180, a Radiotracer for Translocator Protein (TSPO)

“…After CT, approximately 10 MBq of 18 F-GE-180 was administered as an intravenous bolus injection via a tail vein cannula, and a 30-minute dynamic PET was started at the same time with the injection. After PET, 100 µ l of intravenous contrast agent (eXIA160XL, Binitio Biomedical Inc., Ottawa, ON, Canada) was injected, and a high-resolution CT was performed as described in [ 20 ]. The PET images were reconstructed with 2D ordered-subset expectation maximization (OSEM2D) algorithm with two iterations into 2 × 30 s, 4 × 60 s, and 5 × 300 s time frames, and CT images were reconstructed with a Feldkamp-based algorithm.…”

Effects of atorvastatin and diet interventions on atherosclerotic plaque inflammation and [18F]FDG uptake in Ldlr−/−Apob mice

“…Thereafter, the mice were divided into the following interventional groups for an additional 12 resolution CT was performed to visualize the blood vessels. The image reconstruction parameters were similar to those previously described [24]. The PET/CT image analysis was performed using Carimas 2.9 software (Turku PET Centre, Turku, Finland).…”

“…Levels of total cholesterol and triglycerides in the circulation were measured in both baseline and end-ofstudy plasma samples [24]. Two Luminex kits (MILLIPLEX MAP Mouse Cytokine/Chemokine and Mouse Metabolic Hormone Magnetic Bead Panels, Merck Millipore, Billerica, MA, USA) were utilized to assess the inflammatory cytokine interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), as well as the metabolic markers insulin and leptin.…”

“…Paraffin-embedded aortic roots were cut to serial 5 µm sections at the level of the coronary ostia and stained with Movat's pentachrome, or with anti-Mac-3 antibody for macrophages [24]. The total area of intima and the Mac-3-positive area were measured using ImageJ software (NIH, Bethesda, MD, USA).…”