Abstract 3965: Pharmacological Inhibition of CCR2 Decreases Macrophage Infiltration in the Aortic Root of the huCCR2ki / apoE−/− Mouse: MRI Assessment
The purpose of this study was to assess the pharmacological effect of a CCR2 antagonist on macrophage infiltration into atherosclerotic plaque using MRI in an atherosclerotic mouse model. Mice (huCCR2ki/apoE−/−, 22–24 weeks; n=20 per group) were placed on Western diet (Vehicle group) or Western diet + 10 mg/kg/day GSK1344386B (GSK1344386B group). After baseline MR imaging, mice were implanted with osmotic pumps containing Angiotensin II (Ang II, 1000 ng/kg/min) to accelerate lesion formation. After 5 weeks of Ang II administration, thioglycollate was administered (i.p.) to mice (n=4) from each group and a peritoneal lavage was performed 6 hours post-administration to quantitate monocyte recruitment. The remaining mice received USPIO (Combidex®), an MRI contrast agent, for assessment of monocyte/ macrophage infiltration into the atherosclerotic plaque. After imaging, blood was collected for lipid profile, mice were euthanized, liver was weighed, the heart and aorta were perfused fixed in situ and harvested for assessment of plaque via ex vivo MRI and subsequent Mac-2 immunohistochemistry. Following 5 weeks of dietary dosing, there were no significant differences between groups in body and liver weight, or in plasma cholesterol. The peritonitis experiment demonstrated a 92% inhibition of monocyte recruitment in the GSK1344386B group. In vivo MRI revealed a 30% reduction in signal intensity attenuation in the ascending aorta following USPIO administration in the GSK1344386B group. Ex vivo MRI reflected a decrease in aortic root plaque area (0.81±0.05 vs 0.69±0.03 mm2, p<0.05) and increase in aortic root plaque T2* (8.06±0.35 vs 10.11±0.48 ms, p<0.001) while the absolute USPIO uptake (Fe content) in the aortic root was reduced (65.3±22.0 vs 8.3±1.3 ug/g, p<0.05) in the GSK1344386B group. Furthermore, there was a 30% decrease in Mac-2 staining of the aortic roots in the GSK1344386B group. This is the first description for the use of a selective CCR2 antagonist to decrease the rate of atherosclerotic plaque progression. Additionally, the application of a novel MRI contrast agent was used to assess decreased macrophage content in the plaque non-invasively.