Comparison of Contrast Agents for Atherosclerosis Imaging Using Cultured Macrophages: FDG Versus Ultrasmall Superparamagnetic Iron Oxide

Abstract

Various noninvasive imaging methods have been developed to evaluate atherosclerotic plaques. Among them, 18 F-FDG PET and MR imaging with ultrasmall superparamagnetic iron oxide particles (USPIO) have been used to quantify plaque inflammation. Both methods are based on the efficient uptake of FDG and USPIO by macrophages in atherosclerotic lesions. Differently polarized macrophages have been reported to have different characteristics that are involved in the pathologic development of atherosclerosis. M1 polarized macrophages are considered the more proatherogenic phenotype than M2 polarized macrophages. However, little is known regarding the association between macrophage polarization and FDG or USPIO accumulation. In this study, we investigated intracellular FDG and USPIO accumulation in M1 and M2 polarized macrophages. Methods: THP-1 macrophages were differentiated into M1 and M2 polarized macrophages. Under optimal glucose conditions, we investigated the 3 H-labeled FDG uptake in M1 and M2 polarized macrophages. We then investigated intracellular USPIO uptake by M1 and M2 macrophages. Results: We found that M1 polarization, compared with M2 polarization, results in increased intracellular accumulation of FDG. To elucidate the mechanism by which FDG was preferentially accumulated in M1 macrophages, we examined messenger RNA expressions of glucose transporters (GLUTs) and hexokinases, which have pivotal roles in glucose uptake, and glucose-6-phosphatase (G6Pase), which catalyzes the reverse reaction of hexokinase. In M1 macrophages, GLUT-1, GLUT-3, hexokinase 1, and hexokinase 2 were upregulated and G6Pase was downregulated. In contrast to FDG, M1 polarization resulted in decreased intracellular accumulation of USPIO. We found that scavenger receptor A and CD11b, which are involved in USPIO binding and uptake, were significantly downregulated by M1 polarization. Conclusion: Compared with M2, proatherogenic M1 macrophages preferentially accumulated FDG but not USPIO, suggesting that FDG PET is a useful method for the detection of proinflammatory M1 macrophages.

Pharmacological Activation of the Melanocortin System Limits Plaque Inflammation and Ameliorates Vascular Dysfunction in Atherosclerotic Mice

“…We then investigated macrophage phenotype because recent evidence demonstrates that 18 F-FDG uptake is primarily augmented in M1-polarized macrophages expressing proinflammatory markers such as inducible NO synthase, interleukin-1β, and interleukin-6, whereas the uptake is reduced by macrophage M2 polarization. 31 We found that resident macrophages in the lesions of MT-II-treated mice were polarized toward the anti-inflammatory M2 phenotype, thus providing a possible mechanistic explanation for the F-FDG uptake. These findings are supported by other studies proving that pharmacological targeting of MC-Rs suppresses the secretion of proinflammatory mediators by macrophages and induces M2 polarization in experimental models of inflammatory disease.…”

Can the Inflammatory Response Be Evaluated Using 18F-FDG Within Zones of Microvascular Obstruction After Myocardial Infarction?

“…Because in blood the number of neutrophils exceeds the number of monocytes by a factor of approximately 10, it is difficult to conclude what fraction of the labeled white blood cells in the infarcted myocardium is 111 In-labeled neutrophils or 111 In-labeled monocytes. This difficulty is further confounded because it is generally assumed that monocytes are transformed to macrophages (2) and then replicate and accumulate in the infarct region. These transformed monocytes, even if still labeled with 111 In, would have the amount of label per cell diluted during replication.…”

“…Here, we have focused on validating the reliability of 18 F-FDG as a marker of postinfarction inflammation, particularly in light of the markedly compromised flow in areas of recently infarcted myocardium. Adding another layer of complexity to the use of 18 F-FDG in this setting is the need to suppress competing uptake in the normal myocardium and its nonspecificity with respect to inflammation cell type (2,3). Despite these limitations, the combination of PET and MR imaging in 1 device, hybrid PET/MR imaging, would allow one to serially track in 3 dimensions the relationships between scarring and macrophage-based inflammation using late gadolinium enhancement (LGE) and 18 F-FDG, respectively.…”

Radioimmunodetection of Atherosclerotic Lesions Focusing on the Accumulation Mechanism of Immunoglobulin G

“…18 F-FDG is reported to accumulate in macrophages, particularly M1-polarized macrophages in atherosclerotic lesions [23], which is similar to radiolabeled IgG behavior. Therefore, radiolabeled IgG would provide information similarly to 18 F-FDG in the diagnosis of atherosclerosis.…”