Atherosclerotic disease activity is associated with glycolytic enzyme expression across multiple cell types and is...

Positron emission tomography (PET) imaging with the radiolabeled glucose analog fluorodeoxyglucose (¹⁸FDG) is used to monitor atherosclerosis in clinical trials, but there is uncertainty regarding the plaque cell types that accumulate FDG and how uptake is regulated. The long-standing view that ¹⁸FDG is mainly taken up by macrophages is at odds with human and experimental data, and the impact of disease activity on ¹⁸FDG uptake has not been examined directly. To analyze the ability of ¹⁸FDG-PET to monitor disease activity, we developed a model of plaque regression in minipigs with hepatic overexpression of a gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 (PCSK9). Atherosclerosis was induced through 12 months of high-fat feeding in the porcine model. Disease activity was then lowered for 3 months by reducing plasma cholesterol with a low-fat diet alone or in combination with the microsomal transfer protein (MTP) inhibitor BMS-212122. Plaque regression in advanced lesions of the abdominal aorta was evident from reduced lipid content, reduced necrotic core size, and partial resolution of plaque inflammation and was accompanied by a decline in ¹⁸FDG-PET signal. Single-cell gene expression profiling revealed that plaque regression involved substantial down-regulation of genes encoding glycolytic enzymes in smooth muscle cells (SMCs), macrophages, and lymphocytes, which was corroborated by analysis of the plaque cellular proteome. These findings in a large-animal model suggest that ¹⁸FDG-PET can monitor atherosclerosis because of a close association between disease activity and glycolytic enzyme expression in all of the major plaque cell types.