p38 MAPK Inhibition Reduces Aortic Ultrasmall Superparamagnetic Iron Oxide Uptake in a Mouse Model of Atherosclerosis

Abstract

Objective-Ultrasmall superparamagnetic iron oxide (USPIO) contrast agents have been used for noninvasive MRI assessment of atherosclerotic plaque inflammation. The purpose of this study was to noninvasively evaluate USPIO uptake in aorta of apoE Ϫ/Ϫ mice and to determine the effects of Angiotensin II (Ang II) infusion and chronic antiinflammatory treatment with a p38 MAPK inhibitor on this uptake. Methods and Results-ApoEϪ/Ϫ mice were administered saline or Ang II (1.44 mg/kg/d) for 21 days. In vivo MRI assessment of USPIO uptake in the aortic arch was observed in all animals. However, although the Ang II group had significantly higher absolute iron content (1103%, PϽ0.001) in the aortic arch compared with the saline group, the p38 MAPK inhibitor (SB-239063, 150 mg/kg/d) treatment group did not (16%, NS). The in vivo MRI signal intensity was significantly correlated to the absolute iron content in the aortic arch. Histological evaluation of the aortic root lesion area showed colocalization of USPIO with macrophages and a reduction in USPIO but not macrophage content with SB-239063 treatment. Conclusion-The present study demonstrates that noninvasive assessment of USPIO uptake, as a marker for inflammation in murine atherosclerotic plaque, is feasible and that p38 MAPK inhibition attenuates the uptake of USPIO in aorta of Ang II-infused apoE Key Words: atherosclerosis Ⅲ inflammation Ⅲ magnetic resonance imaging Ⅲ USPIO Ⅲ apoE Ϫ/Ϫ Ⅲ p38 MAPK A lthough experimental evidence linking inflammatory processes to the fate of the atherosclerotic plaque development exists, it is difficult to examine these processes noninvasively and to provide convincing links between preclinical and clinical studies. In this regard, ultrasmall superparamagnetic iron oxide (USPIO) contrast agents, optimized for uptake by the mononuclear phagocytic system, 1-3 are of particular interest for translational cardiovascular research. These agents have been used for noninvasive MRI assessment of atherosclerotic plaque inflammation in humans 4 -6 as well as hypercholesterolemic balloon-injured NZW 7 and WHHL 8 -11 rabbits. However, descriptions of USPIO use in extensively-studied murine genetic models of atherosclerosis have been limited. Investigators have used other targeted 12,13 and nontargeted 14 approaches to noninvasively assess plaque burden or inflammation in atherosclerotic mouse models. Additionally, superparamagnetic iron oxide (SPIO) has been used to quantify monocyte recruitment histologically in atherosclerotic lesions of the apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mouse. 15 In that study, acute administration of tumor necrosis factor (TNF), interleukin (IL)-1␤, and interferon (INF)-␥ was shown to stimulate SPIO uptake by 4-fold in plaque. Although this study supports the hypothesis that plaque targeting of the USPIO contrast agent in mouse is facilitated by monocyte recruitment or activation of macrophage phagocytosis, noninvasive assessment of USPIO uptake in mouse atherosclerotic lesions has not been reported. Recent evidence sugg...

Flow‐enhanced off‐resonance saturation for remote detection of iron‐based contrast agents

“…The frequency shifts produced by iron-loaded plaques in vivo are not expected to be as strong and localized as in our phantom, mainly due to lower concentration of the contrast agent and the spatial extension of plaques. However, in vivo, images of mice and rabbits model (6,8) showed lumens with dark regions in the vicinity of plaques at relatively moderate gradient echo times, so-called functional stenosis (23), which is illustrated in Fig. 6a.…”

“…Therefore, they can be identified by signal voids, which are caused by static dephasing induced by the off-resonance field (3). Due to this contrast mechanism, atherosclerotic plaques have been successfully visualized in the aortic vessels of apolipoprotein E knock-out (ApoE À/À) mice (8), hyperlipidemic rabbits (6), and human carotid (9,10) and aortic vessels (11). This work focuses on improving methods for plaque detection using superparamagnetic iron oxide particle/ USPIO contrast agents.…”

Optimization of high‐resolution USPIO magnetic resonance imaging at 4.7 T using novel phantom with minimal structural interference

“…To emphasize small concentrations, natural logarithms of the dilution factor (eg, ln(1/20480) for concentration 17.1 nmol Fe/mL) were used as weights in calculating the weighted mean parameters (see Eq. [3] in Appendix C). To calculate the weighted mean flip angle for FISP, the flip angle yielding the most negative CNR saline-CM for each concentration was used.…”

“…Circulating USPIOs are primarily phagocytosed by white blood cells of the monocyte/macrophage cell line (2). Therefore, accumulation of USPIOs reflects recruitment of macrophages (or phagocytic activity of macrophages) and is an indication of inflammation (3).…”

Contrast-enhanced MR imaging of atherosclerosis using citrate-coated superparamagnetic iron oxide nanoparticles: calcifying microvesicles as imaging target for plaque characterization

“…1,[3][4][5]9 Available preclinical studies and clinical trials in humans suggest that the optimal time for detecting the MRI signal loss induced in atherosclerotic lesions using dextran-or other polymercoated USPIO (eg, ferumoxtran-10, ferumoxytol, or P904), is 24 to 48 hours after IV administration. [3][4][5][11][12][13] This is clearly not optimal for ensuring a smooth workflow in the routine clinical setting. Several cell culture studies have shown that cellular uptake of citrate-coated iron oxide nanoparticles is faster and quantitatively superior to that of polymer-coated iron oxide nanoparticles.…”