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(Circulation. 2003;107:1545.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Superparamagnetic Iron Oxide–Based Method for Quantifying Recruitment of Monocytes to Mouse Atherosclerotic Lesions In Vivo

Enhancement by Tissue Necrosis Factor-, Interleukin-1ß, and Interferon-

Silvio Litovsky, MD; Mohammad Madjid, MD; Alireza Zarrabi, MD; S. Ward Casscells, MD; James T. Willerson, MD; Morteza Naghavi, MD

From the Center for Vulnerable Plaque Research, Texas Heart Institute at St Luke’s Episcopal Hospital; the Division of Cardiology, The University of Texas–Houston Health Science Center at Houston; and President Bush Center for Cardiovascular Health at Memorial Hermann Hospital, Houston, Tex.

Correspondence to Morteza Naghavi, MD, Division of Cardiology, The University of Texas–Houston Health Science Center, 6431 Fannin, MSB 1.246, Houston, TX 77030. E-mail mnaghavi{at}vp.org

Background— It has been found recently that the MRI contrast agent superparamagnetic iron oxide (SPIO) localizes to aortic atherosclerotic plaques. We therefore asked whether SPIO might be used to monitor monocyte recruitment into aortic atherosclerotic plaques.

Methods and Results— Eleven female apo E knockout (K/O) mice, each 11 months old, were divided into 2 groups. Six mice received tissue necrosis factor- (0.2 µg IP once), interleukin-1ß (0.2 µg IP once), and interferon- (100 U/g per day IP for 5 days); 5 received 0.5 mL saline containing1% BSA and served as sham-treated atherosclerotic controls. Two wild-type C57BL/6 mice served as sham-treated nonatherosclerotic controls. Three hours after initial cytokine or sham treatment, all mice received SPIO by intravenous injection (1 mmol/kg iron). Six days later, all mice were euthanized, the hearts and aortas were perfused under physiological pressure, and the entire aortas were studied histologically. Atherosclerotic plaques in cytokine-treated mice contained more iron-positive macrophages per cross section than did those in sham-treated apo E K/O control mice (42±11.8 versus 11.6±5.9) (P<0.0001). Iron-laden macrophages were present either in subendothelial plaque surfaces or in thin layers overlying the internal elastic lamina, often at the edges of atherosclerotic plaques. No iron deposition was seen in aortas of the wild-type nonatherosclerotic control mice. Immunocytochemistry showed mostly macrophages and few T lymphocytes in atherosclerotic plaques of cytokine-treated mice.

Conclusions— SPIO allows detection of iron-laden macrophages in the aortic subendothelium of apo E–deficient mice under basal conditions and monitoring of monocyte recruitment after cytokine injection.

Key Words: atherosclerosis • imaging • magnetic resonance imaging • leukocytes • interleukins

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