Regression of inflammation in atherosclerosis by the LXR agonist R211945: a noninvasive assessment and comparison with atorvastatin.
OBJECTIVE
The aim of this study was to noninvasively detect the anti-inflammatory properties of the novel liver X receptor agonist R211945.


BACKGROUND
R211945 induces reversal cholesterol transport and modulates inflammation in atherosclerotic plaques. We aimed to characterize with (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) and dynamic contrast-enhanced cardiac magnetic resonance (DCE-CMR) inflammation and neovascularization, respectively, in atherosclerotic plaques with R211945 treatment compared with atorvastatin treatment and a control.


METHODS
Twenty-one atherosclerotic New Zealand white rabbits were divided into 3 groups (control, R211945 [3 mg/kg orally], and atorvastatin [3 mg/kg orally] groups). All groups underwent (18)F-FDG-PET/CT and DCE-CMR at baseline and at 1 and 3 months after treatment initiation. Concomitantly, serum metabolic parameters and histology were assessed. For statistical analysis, continuous DCE-CMR and PET/CT outcomes were modeled as linear functions of time by using a linear mixed model, whereas the histological data, animal characteristics data, and nonlinear regression imaging data were analyzed with a 2-tailed Student t test.


RESULTS
(18)F-FDG-PET/CT detected a decrease in mean and maximum standard uptake values (SUV) over time in the R211945 group (both p = 0.001), indicating inflammation regression. The atorvastatin group displayed no significant change (p = 0.371 and p = 0.600, respectively), indicating no progression or regression. The control group demonstrated an increase in SUV (p = 0.01 and p = 0.04, respectively), indicating progression. There was a significant interaction between time and group for mean and maximum SUV (p = 0.0003 and p = 0.0016, respectively) . DCE-CMR detected a trend toward difference (p = 0.06) in the area under the curve in the atorvastatin group, suggesting a decrease in neovascularization. There was no significant interaction between time and group (p = 0.6350 and p = 0.8011, respectively). Macrophage and apolipoprotein B immunoreactivity decreased in the R211945 and atorvastatin groups (p < 0.0001 and p = 0.0004, respectively), and R211945 decreased oxidized phospholipid immunoreactivity (p = 0.02).


CONCLUSIONS
Noninvasive imaging with (18)F-FDG-PET/CT and DCE-CMR and histological analysis demonstrated significant anti-inflammatory effects of the LXR agonist R211945 compared with atorvastatin. The results suggest a possible role for LXR agonists in the treatment of atherosclerosis.
Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, New York, NY, USA.
Esad
E
Vucic
Claudia
C
Calcagno
Stephen D
SD
Dickson
James H F
JH
Rudd
Katsumi
K
Hayashi
Jan
J
Bucerius
Erin
E
Moshier
Jessica S
JS
Mounessa
Michelle
M
Roytman
Matthew J
MJ
Moon
James
J
Lin
Sarayu
S
Ramachandran
Tatsuo
T
Tanimoto
Karen
K
Brown
Masakatsu
M
Kotsuma
Sotirios
S
Tsimikas
Edward A
EA
Fisher
Klaas
K
Nicolay
Valentin
V
Fuster
Zahi A
ZA
Fayad
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D000069059:Atorvastatin; D018450:Disease Progression; D019788:Fluorodeoxyglucose F18; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D064847:Multimodal Imaging; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011758:Pyrroles / Q000627:therapeutic use*; D011817:Rabbits; D019275:Radiopharmaceuticals; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
D001055:Apolipoproteins B; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011758:Pyrroles; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D000069059:Atorvastatin