Pharmacological inhibition of C-C chemokine receptor 2 decreases macrophage infiltration in the aortic root of the human C-C chemokine receptor 2/apolipoprotein E-/- mouse: magnetic resonance imaging assessment.
Purpose- This study assessed the pharmacological effect of a novel selective C-C chemokine receptor (CCR) 2 antagonist (GSK1344386B) on monocyte/macrophage infiltration into atherosclerotic plaque using magnetic resonance imaging (MRI) in an atherosclerotic mouse model.


RESULTS
Apolipoprotein E(-/-) mice expressing human CCR2 were fed a Western diet (vehicle group) or a Western diet plus10 mg/kg per day of GSK1344386B (GSK1344386B group). After the baseline MRI, mice were implanted with osmotic pumps containing angiotensin II, 1000 ng/kg per minute, to accelerate lesion formation. After five weeks of angiotensin II administration, mice received ultrasmall superparamagnetic iron oxide, an MRI contrast agent for the assessment of monocyte/macrophage infiltration to the plaque, and underwent imaging. After imaging, mice were euthanized, and the heart and aorta were harvested for ex vivo MRI and histopathological examination. After 5 weeks of dietary dosing, there were no significant differences between groups in body or liver weight or plasma cholesterol concentrations. An in vivo MRI reflected a decrease in ultrasmall superparamagnetic iron oxide contrast agent uptake in the aortic arch of the GSK1344386B group (P<0.05). An ex vivo MRI of the aortic root also reflected decreased ultrasmall superparamagnetic iron oxide uptake in the GSK1344386B group and was verified by absolute iron analysis (P<0.05). Although there was no difference in aortic root lesion area between groups, there was a 30% reduction in macrophage area observed in the GSK1344386B group (P<0.05).


CONCLUSIONS
An MRI was used to noninvasively assess the decreased macrophage content in the atherosclerotic plaque after selective CCR2 inhibition.
Olzinski
Alan R
AR
Cardiovascular and Urogenital Center of Excellence in Drug Discovery, King of Prussia, PA, USA.
Turner
Gregory H
GH
Bernard
Roberta E
RE
Karr
Heather
H
Cornejo
Carla A
CA
Aravindhan
Karpagam
K
Hoang
Bao
B
Ringenberg
Michael A
MA
Qin
Pu
P
Goodman
Krista B
KB
Willette
Robert N
RN
Macphee
Colin H
CH
Jucker
Beat M
BM
Sehon
Clark A
CA
Gough
Peter J
PJ
D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001018:Aortic Diseases / Q000178:diet therapy* / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003287:Contrast Media; D003911:Dextrans; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D052203:Ferrosoferric Oxide; D006801:Humans; D007150:Immunohistochemistry; D015918:Infusion Pumps, Implantable; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009287:Naphthyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D010538:Peritonitis / Q000276:immunology / Q000517:prevention & control; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; C515334:CCR2 protein, human; D003287:Contrast Media; D003911:Dextrans; D004041:Dietary Fats; D058185:Magnetite Nanoparticles; C547061:N-(3-(1-methylethyl)-3-((3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclopentyl)tetrahydro-2H-pyran-4-amine; D009287:Naphthyridines; D054390:Receptors, CCR2; C097921:ferumoxtran-10; D000804:Angiotensin II; D052203:Ferrosoferric Oxide