← Back to Search
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
A. Olzinski, G. Turner, Roberta E. Bernard, Heather Karr, C. Cornejo, K. Aravindhan, B. Hoang, M. Ringenberg, P. Qin, K. Goodman, R. Willette, C. Macphee, B. Jucker, C. A. Sehon, P. Gough
Published 2010 · Medicine, Biology
Save to my Library
Download PDFAnalyze on Scholarcy
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. Methods and 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). Conclusion—An MRI was used to noninvasively assess the decreased macrophage content in the atherosclerotic plaque after selective CCR2 inhibition.
This paper references
Noninvasive Vascular Cell Adhesion Molecule-1 Imaging Identifies Inflammatory Activation of Cells in Atherosclerosis
M. Nahrendorf (2006)
Angiotensin II Amplifies Macrophage-Driven Atherosclerosis
Ayabe Nobuhiko (2004)
Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI
Vardan Amirbekian (2007)
Microanalysis of non-heme iron in animal tissues.
C. Rebouche (2004)
Myocardial protection with calcium-channel blockers during ischaemia and reperfusion by PTCA.
S. Chouairi (1995)
Differential effects of angiotensin II on atherogenesis at the aortic sinus and descending aorta of apolipoprotein-E-deficient mice.
Y. Zhou (2005)
Current Concepts of the Pathogenesis of the Acute Coronary Syndromes
P. Libby (2001)
Why do plaques rupture? Circulation
E. Falk (1992)
Identifying Inflamed Carotid Plaques Using In Vivo USPIO-Enhanced MR Imaging to Label Plaque Macrophages
R. Trivedi (2006)
covery and pharmacological characterization of a novel rodent - active CCR 2 antagonist , INCB 3344
CM Brodmerkel (2005)
A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity.
M. Baba (1999)
Magnetic Resonance Imaging of Atherosclerotic Plaque With Ultrasmall Superparamagnetic Particles of Iron Oxide in Hyperlipidemic Rabbits
S. Ruehm (2001)
Superparamagnetic iron oxide-enhanced MRI of atherosclerotic plaques in Watanabe hereditable hyperlipidemic rabbits.
S. A. Schmitz (2000)
Ferumoxtran-10–Enhanced MRI of the Hypercholesterolemic Rabbit Aorta: Relationship Between Signal Loss and Macrophage Infiltration
F. Hyafil (2006)
Magnetic resonance imaging of experimental atherosclerotic plaque: Comparison of two ultrasmall superparamagnetic particles of iron oxide
C. Herborn (2006)
Accumulation of Ultrasmall Superparamagnetic Particles of Iron Oxide in Human Atherosclerotic Plaques Can Be Detected by In Vivo Magnetic Resonance Imaging
M. E. Kooi (2003)
The role of chemokines in atherosclerosis: recent evidence from experimental models and population genetics
C. Bursill (2004)
Absence of CC chemokine receptor-2 reduces atherosclerosis in apolipoprotein E-deficient mice.
T. Dawson (1999)
Resistance to Experimental Autoimmune Encephalomyelitis in Mice Lacking the Cc Chemokine Receptor (Ccr2)
L. Izikson (2000)
A CCR2/CCR5 Antagonist Attenuates an Increase in Angiotensin II-Induced CD11b+ Monocytes from Atherogenic ApoE−/− Mice
T. Major (2008)
Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes. A regulatory role for plasma LDL.
K. H. Han (1998)
p38 MAPK Inhibition Reduces Aortic Ultrasmall Superparamagnetic Iron Oxide Uptake in a Mouse Model of Atherosclerosis: MRI Assessment
J. Morris (2008)
Differential uptake of ferumoxtran‐10 and ferumoxytol, ultrasmall superparamagnetic iron oxide contrast agents in rabbit: Critical determinants of atherosclerotic plaque labeling
A. D. Yancy (2005)
Magnetic resonance imaging of atherosclerotic plaques using superparamagnetic iron oxide particles
S. A. Schmitz (2001)
Cloning and Functional Expression of mCCR2, a Murine Receptor for the C-C Chemokines JE and FIC (*)
T. Kurihara (1996)
Discovery and Pharmacological Characterization of a Novel Rodent-Active CCR2 Antagonist, INCB3344
Carrie M Brodmerkel (2005)
MLN1202, a novel CCR2 antagonist, decreases C-reactive protein in patients at risk for atherosclerotic cardiovascular disease in a double blind placebo controlled study. Circulation
M Davidson (2007)
Propagermanium Reduces Atherosclerosis in Apolipoprotein E Knockout Mice via Inhibition of Macrophage Infiltration
T. Yamashita (2002)
Macrophage Endocytosis of Superparamagnetic Iron Oxide Nanoparticles: Mechanisms and Comparison of Ferumoxides and Ferumoxtran-10
I. Raynal (2004)
Plaque pathology and coronary thrombosis in the pathogenesis of acute coronary syndromes.
J. Zhou (1999)
The interface of atherosclerosis and thrombosis: basic mechanisms
P. Libby (1998)
Migratory fate and differentiation of blood monocyte subsets.
F. Tacke (2006)
Aortic Dissection Precedes Formation of Aneurysms and Atherosclerosis in Angiotensin II-Infused, Apolipoprotein E-Deficient Mice
Kiran Y. Saraff (2003)
MR imaging of murine arthritis using ultrasmall superparamagnetic iron oxide particles.
B. Dardzinski (2001)
Chemokines in Atherosclerosis , Thrombosis , and Vascular Biology
A. Schober (2008)
Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata.
F. Swirski (2007)
Cellular Imaging of Inflammation in Atherosclerosis Using Magnetofluorescent Nanomaterials
F. Jaffer (2006)
Coronary plaque disruption.
E. Falk (1995)
Why do plaques rupture?
E. Falk (1992)
Stabilization of atherosclerotic plaques: New mechanisms and clinical targets
P. Libby (2002)
in apolipoprotein E - deficient mice
N Saederup (1999)
Acute coronary thrombosis--the role of plaque disruption and its initiation and prevention.
M. Davies (1995)
MLN 1202 , a novel CCR 2 antagonist , decreases C - reactive protein in patients at risk for atherosclerotic cardiovascular disease in a double blind placebo controlled study
K Saraff (2007)
Targeted replacement of rodent CCR2 with the human orthologue CCR2B: A mouse model for in vivo analysis of human target‐selective small molecule MCP‐1 receptor antagonists
H. M. Prosser (2002)
Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis
L. Boring (1998)
Recent developments in CCR2 antagonists
M. Xia (2009)
Fractalkine Deficiency Markedly Reduces Macrophage Accumulation and Atherosclerotic Lesion Formation in CCR2−/− Mice: Evidence for Independent Chemokine Functions in Atherogenesis
Noah Saederup (2008)
Transplantation of Monocyte CC-Chemokine Receptor 2-Deficient Bone Marrow Into ApoE3-Leiden Mice Inhibits Atherogenesis
Jian Guo (2003)
Diet induction of monocyte chemoattractant protein-1 and its impact on obesity.
Airu Chen (2005)
The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease.
T. Tang (2009)
HIV Entry Inhibitor TAK-779 Attenuates Atherogenesis in Low-Density Lipoprotein Receptor–Deficient Mice
E. J. V. van Wanrooij (2005)
MR imaging of phagocytosis in experimental gliomas.
C. Zimmer (1995)
This paper is referenced by
Peptide Inhibitor of CXCL4–CCL5 Heterodimer Formation, MKEY, Inhibits Experimental Aortic Aneurysm Initiation and Progression
Y. Iida (2013)
Pharmacological Inhibition of the Chemokine Receptor, CX3CR1, Reduces Atherosclerosis in Mice
L. Poupel (2013)
Mechanisms of the Renin Angiotensin System Influencing Atherosclerosis
H. Lu (2015)
Chapter 2 Cytokines and Immune Responses in Murine Atherosclerosis
P. Kusters (2019)
The regulation and importance of monocyte chemoattractant protein-1
V. Bianconi (2018)
Targeting chemokine receptors in chronic inflammatory diseases: an extensive review.
P. Koelink (2012)
PET imaging of aortic atherosclerosis: Is combined imaging of plaque anatomy and function an amaranthine quest or conceivable reality?
G. Small (2011)
Site-Directed Mutagenesis of the CC Chemokine Binding Protein 35K-Fc Reveals Residues Essential for Activity and Mutations That Increase the Potency of CC Chemokine Blockade
G. White (2011)
Distinct functions of CXCR4, CCR2, and CX3CR1 direct dendritic cell precursors from the bone marrow to the lung
H. Nakano (2017)
Orally-Administered Chemokine Receptor CCR2 Antagonist CCX140-B in Type 2 Diabetes: A Pilot Double-Blind, Randomized Clinical Trial
M. Hanefeld (2012)
An overview of the innate and adaptive immune system in atherosclerosis
Mina Mohmmad‐Rezaei (2020)
CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice.
T. Sullivan (2013)
Monocyte subtypes and the CCR2 chemokine receptor in cardiovascular disease.
C. França (2017)
Characterization of CCX140-B, an orally bioavailable antagonist of the CCR2 chemokine receptor, for the treatment of type 2 diabetes and associated complications.
T. Sullivan (2012)
Mouse: Magnetic Resonance Imaging Assessment - / - E Infiltration in the Aortic Root of the Human C-C Chemokine Receptor 2/Apolipoprotein Pharmacological Inhibition of C-C Chemokine Receptor 2 Decreases Macrophage
Robert Nicholas Willette (2012)
Molecular Imaging of Macrophage Enzyme Activity in Cardiac Inflammation
M. Ali (2014)
Increased C-C Chemokine Receptor 2 Gene Expression in Monocytes of Severe Obstructive Sleep Apnea Patients and under Intermittent Hypoxia
L. Chuang (2014)
Cytokines in atherosclerosis: Key players in all stages of disease and promising therapeutic targets
D. Ramji (2015)
Multimodal imaging approach to examine biodistribution kinetics of Cabotegravir (GSK1265744) long acting parenteral formulation in rat
B. Jucker (2017)
Cytokines: roles in atherosclerosis disease progression and potential therapeutic targets.
J. Moss (2016)
Cytokines and Immune Responses in Murine Atherosclerosis.
P. Kusters (2015)
CCR 2 antagonist CCX 140-B provides renal and glycemic benefits in diabetic transgenic human CCR 2 knockin mice
T. Sullivan (2013)
Applications of Preclinical MRI/MRS in the Evaluation of Drug Efficacy and Safety
Thomas M. Bocan (2015)
A novel C-C chemokine receptor 2 antagonist prevents progression of albuminuria and atherosclerosis in mouse models.
Masayuki Okamoto (2012)
CCR2 expression on circulating monocytes is associated with arterial wall inflammation assessed by 18F-FDG PET/CT in patients at risk for cardiovascular disease
S. Verweij (2018)
Molecular MRI of Atherosclerosis with USPIO
M. Sigovan (2012)
Innate immune system cells in atherosclerosis.
L. Chávez-Sánchez (2014)
A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy
I. Bot (2017)
Monocyte Chemoattractant Protein-1 Deficiency Protects Against Visceral Fat–Induced Atherosclerosis
M. Öhman (2010)
CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges
G. White (2013)
Photodynamic Therapy Using a Protease-Mediated Theranostic Agent Reduces Cathepsin-B Activity in Mouse Atheromata In Vivo
Soo-Min Shon (2013)
Progress in the discovery of CC chemokine receptor 2 antagonists, 2009 – 2012
P. Carter (2013)See more