Regression of inflammation in atherosclerosis by the LXR agonist R211945

A noninvasive assessment and comparison with atorvastatin

Esad Vucic, Claudia Calcagno, Stephen D. Dickson, James H.F. Rudd, Katsumi Hayashi, Jan Bucerius, Erin Moshier, Jessica S. Mounessa, Michelle Roytman, Matthew Moon, James Lin, Sarayu Ramachandran, Tatsuo Tanimoto, Karen Brown, Masakatsu Kotsuma, Sotirios Tsimikas, Edward A. Fisher, Klaas Nicolay, Valentin Fuster, Zahi A. Fayad

Research output: Contribution to journalReview article

Abstract

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 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. 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-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. 18F-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 18F-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.

Original languageEnglish (US)
Pages (from-to)819-828
Number of pages10
JournalJACC: Cardiovascular Imaging
Volume5
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

Fingerprint

Atherosclerosis
Inflammation
Magnetic Resonance Spectroscopy
Tomography
Atherosclerotic Plaques
Anti-Inflammatory Agents
Control Groups
Fluorodeoxyglucose F18
Apolipoproteins B
Therapeutics
Area Under Curve
Atorvastatin Calcium
Linear Models
Phospholipids
Histology
Macrophages
Cholesterol
Students
Rabbits
Serum

Keywords

  • a.u.
  • ABCA1
  • arbitrary units
  • area under the curve
  • ATP-binding cassette transporter A1
  • AUC
  • computed tomography
  • CT
  • DCE-CMR
  • dynamic contrast-enhanced cardiac magnetic resonance
  • FDG
  • fluorodeoxyglucose
  • liver X receptor
  • LXR
  • PET
  • positron emission tomography
  • standard uptake value
  • SUV
  • vascular endothelial growth factor
  • VEGF

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Cardiology and Cardiovascular Medicine

Cite this

Regression of inflammation in atherosclerosis by the LXR agonist R211945 : A noninvasive assessment and comparison with atorvastatin. / Vucic, Esad; Calcagno, Claudia; Dickson, Stephen D.; Rudd, James H.F.; Hayashi, Katsumi; Bucerius, Jan; Moshier, Erin; Mounessa, Jessica S.; Roytman, Michelle; Moon, Matthew; Lin, James; Ramachandran, Sarayu; Tanimoto, Tatsuo; Brown, Karen; Kotsuma, Masakatsu; Tsimikas, Sotirios; Fisher, Edward A.; Nicolay, Klaas; Fuster, Valentin; Fayad, Zahi A.

In: JACC: Cardiovascular Imaging, Vol. 5, No. 8, 08.2012, p. 819-828.

Research output: Contribution to journalReview article

Vucic, E, Calcagno, C, Dickson, SD, Rudd, JHF, Hayashi, K, Bucerius, J, Moshier, E, Mounessa, JS, Roytman, M, Moon, M, Lin, J, Ramachandran, S, Tanimoto, T, Brown, K, Kotsuma, M, Tsimikas, S, Fisher, EA, Nicolay, K, Fuster, V & Fayad, ZA 2012, 'Regression of inflammation in atherosclerosis by the LXR agonist R211945: A noninvasive assessment and comparison with atorvastatin', JACC: Cardiovascular Imaging, vol. 5, no. 8, pp. 819-828. https://doi.org/10.1016/j.jcmg.2011.11.025
Vucic, Esad ; Calcagno, Claudia ; Dickson, Stephen D. ; Rudd, James H.F. ; Hayashi, Katsumi ; Bucerius, Jan ; Moshier, Erin ; Mounessa, Jessica S. ; Roytman, Michelle ; Moon, Matthew ; Lin, James ; Ramachandran, Sarayu ; Tanimoto, Tatsuo ; Brown, Karen ; Kotsuma, Masakatsu ; Tsimikas, Sotirios ; Fisher, Edward A. ; Nicolay, Klaas ; Fuster, Valentin ; Fayad, Zahi A. / Regression of inflammation in atherosclerosis by the LXR agonist R211945 : A noninvasive assessment and comparison with atorvastatin. In: JACC: Cardiovascular Imaging. 2012 ; Vol. 5, No. 8. pp. 819-828.
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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

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 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. 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-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. 18F-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 18F-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 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. 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-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. 18F-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 18F-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 - a.u.

KW - ABCA1

KW - arbitrary units

KW - area under the curve

KW - ATP-binding cassette transporter A1

KW - AUC

KW - computed tomography

KW - CT

KW - DCE-CMR

KW - dynamic contrast-enhanced cardiac magnetic resonance

KW - FDG

KW - fluorodeoxyglucose

KW - liver X receptor

KW - LXR

KW - PET

KW - positron emission tomography

KW - standard uptake value

KW - SUV

KW - vascular endothelial growth factor

KW - VEGF

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