TY - JOUR
T1 - Regression of inflammation in atherosclerosis by the LXR agonist R211945
T2 - A noninvasive assessment and comparison with atorvastatin
AU - Vucic, Esad
AU - Calcagno, Claudia
AU - Dickson, Stephen D.
AU - Rudd, James H.F.
AU - Hayashi, Katsumi
AU - Bucerius, Jan
AU - Moshier, Erin
AU - Mounessa, Jessica S.
AU - Roytman, Michelle
AU - Moon, Matthew J.
AU - Lin, James
AU - Ramachandran, Sarayu
AU - Tanimoto, Tatsuo
AU - Brown, Karen
AU - Kotsuma, Masakatsu
AU - Tsimikas, Sotirios
AU - Fisher, Edward A.
AU - Nicolay, Klaas
AU - Fuster, Valentin
AU - Fayad, Zahi A.
PY - 2012/8
Y1 - 2012/8
N2 - The aim of this study was to noninvasively detect the anti-inflammatory properties of the novel liver X receptor agonist R211945. 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. 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-FDGPET/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. 18 F-FDGPET/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). Noninvasive imaging with 18 F-FDGPET/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.
AB - The aim of this study was to noninvasively detect the anti-inflammatory properties of the novel liver X receptor agonist R211945. 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. 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-FDGPET/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. 18 F-FDGPET/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). Noninvasive imaging with 18 F-FDGPET/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.
KW - ABCA1
KW - ATP-binding cassette transporter A1
KW - AUC
KW - CT
KW - DCE-CMR
KW - FDG
KW - LXR
KW - PET
KW - SUV
KW - VEGF
KW - a.u.
KW - arbitrary units
KW - area under the curve
KW - computed tomography
KW - dynamic contrast-enhanced cardiac magnetic resonance
KW - fluorodeoxyglucose
KW - liver X receptor
KW - positron emission tomography
KW - standard uptake value
KW - vascular endothelial growth factor
UR - http://www.scopus.com/inward/record.url?scp=84865100546&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865100546&partnerID=8YFLogxK
U2 - 10.1016/j.jcmg.2011.11.025
DO - 10.1016/j.jcmg.2011.11.025
M3 - Article
C2 - 22897996
AN - SCOPUS:84865100546
SN - 1936-878X
VL - 5
SP - 819
EP - 828
JO - JACC: Cardiovascular Imaging
JF - JACC: Cardiovascular Imaging
IS - 8
ER -