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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:265.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

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

MRI Assessment

Joanne B. Morris; Alan R. Olzinski; Roberta E. Bernard; Karpagam Aravindhan; Rosanna C. Mirabile; Rogely Boyce; Robert N. Willette; Beat M. Jucker

From Laboratory Animal Science (J.B.M.), Cardiovascular and Urogenital Center of Excellence in Drug Discovery (A.R.O., R.E.B., K.A., R.N.W., B.M.J.), and Safety Assessment (R.C.M., R.B.), GlaxoSmithKline, King of Prussia, Pa.

Correspondence to Beat M. Jucker, PhD, GlaxoSmithKline, Mail Code: UW2510, 709 Swedeland Rd, King of Prussia, PA 19406. E-mail beat.m.jucker{at}gsk.com

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^–/– 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— ApoE^–/– 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 (103%, P<0.001) in the aortic arch compared with the saline group, the p38 MAPK inhibitor (SB-239063, 150 mg/kg/d) treatment group did not (6%, 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^–/– mice.

The purpose of this study was to noninvasively evaluate USPIO uptake in aorta of Ang II–administered apoE^–/– mice treated with a p38 MAPK inhibitor (SB-239063). MRI assessment of USPIO uptake, as a marker for inflammation in atherosclerotic plaque, is feasible and p38 MAPK inhibition attenuates the uptake of USPIO in aorta of Ang II–infused apoE^–/– mice.

Key Words: atherosclerosis • inflammation • magnetic resonance imaging • USPIO • apoE^–/– • p38 MAPK

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