Regression of Inflammation in Atherosclerosis by the LXR Agonist R211945

Abstract

OBJECTIVES 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 18F-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 18F-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 18F-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 18F-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.

The Ins and Outs of Myeloid Cells in Atherosclerosis

“…While some studies describe leukocyte egress as a beneficial effect for solving atherosclerosis [39, 44, 45], others point out that reversed migrated neutrophils promote systemic inflammation [42, 43, 46]. Apoptosis of reversed transmigrated neutrophils is delayed, meaning that those cells can circulate for a prolonged time.…”

Atherosclerotic Plaque Destabilization

“…120 In contrast, R211945, the novel liver X receptor agonist, led to plaque regression in a rabbit model of atherosclerosis without secondary adverse side effects. 121 However, the oral administration of sphingosine-1-phosphate mimetic, FTY720, dampens NC formation and plaque size.…”

99mTc-cAbVCAM1-5 Imaging Is a Sensitive and Reproducible Tool for the Detection of Inflamed Atherosclerotic Lesions in Mice

“…Several studies have investigated the potential of 18 F-FDG for the noninvasive assessment of treatment efficacy. Such potential has been validated in rabbits using the antioxidant probucol (26), thereby allowing the use of 18 F-FDG for the evaluation of novel therapeutics in preclinical studies (27,28) and clinical studies (12,29). However, high myocardial uptake remains a potential limitation for the imaging of coronary lesions with 18 F-FDG despite the use of imaging protocols aimed at reducing myocardial tracer uptake (30).…”