p38 MAPK inhibition reduces aortic ultrasmall superparamagnetic iron oxide uptake in a mouse model of atherosclerosis: MRI assessment.
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.


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 (increased 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 (increased 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.


CONCLUSIONS
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.
Morris
Joanne B
JB
GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA 19406, USA.
Olzinski
Alan R
AR
Bernard
Roberta E
RE
Aravindhan
Karpagam
K
Mirabile
Rosanna C
RC
Boyce
Rogely
R
Willette
Robert N
RN
Jucker
Beat M
BM
D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001011:Aorta / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000175:diagnosis; D003287:Contrast Media / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005240:Feasibility Studies; D052203:Ferrosoferric Oxide / Q000493:pharmacokinetics; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000175:diagnosis; D018810:Magnetic Resonance Angiography / Q000379:methods*; D008297:Male; D053768:Metal Nanoparticles; D051379:Mice; D018345:Mice, Knockout; D011743:Pyrimidines / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D001057:Apolipoproteins E; D003287:Contrast Media; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011743:Pyrimidines; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063; D052203:Ferrosoferric Oxide