Synergistic effect of liver X receptor activation and simvastatin on plaque regression and stabilization: an magnetic resonance imaging study in a model of advanced atherosclerosis

Eur Heart J. 2012 Jan;33(2):264-73. doi: 10.1093/eurheartj/ehr136. Epub 2011 May 23.


Aims: The aim of this study was to investigate the effects of liver X receptors (LXRs)-β preferential activation by LXR-623 (WAY-252623), a novel LXRs agonist, on plaque progression/regression in a rabbit model of advanced atherosclerosis.

Methods and results: Advanced atherosclerosis was induced in New Zealand White Rabbits (n= 41). At the end of atherosclerosis induction, animals underwent a baseline magnetic resonance imaging (MRI) and were randomized to receive LXR-623 (1.5, 5, or 15 mg/kg/day), simvastatin (5 mg/kg/day), or placebo. The combination of LXR-1.5/simvastatin was also tested. After a final MRI, animals were euthanized and their aortas processed for further analysis. Simvastatin significantly reduced lesion progression (-25%; P< 0.01) in comparison with the placebo group. A similar effect was observed in the LXR-1.5 and -5 groups. A significant regression (16.5%; P< 0.01) of existing atherosclerosis was observed in the LXR-1.5/simvastatin group. Histological and molecular analysis showed plaque stabilization in the animals treated with the LXR-1.5 and -5, and LXR-1.5/simvastatin. The effects of LXR-623 were observed in the presence of a non-significant effect on total-cholesterol, low-density lipoproteins-cholesterol, and triglyceride levels.

Conclusion: The results of the present study show that LXR-623 significantly reduces the progression of atherosclerosis and induces plaque regression in combination with simvastatin. These observations could drive future development of novel anti-atherosclerotic therapeutic approaches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticholesteremic Agents / pharmacology*
  • Aorta, Abdominal
  • Aortic Diseases / drug therapy
  • Aortic Diseases / metabolism
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / metabolism
  • Chemokine CCL2 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Disease Progression
  • Drug Combinations
  • Drug Synergism
  • Indazoles / pharmacology*
  • Liver X Receptors
  • Magnetic Resonance Angiography
  • Orphan Nuclear Receptors / antagonists & inhibitors
  • Orphan Nuclear Receptors / drug effects*
  • Plaque, Atherosclerotic / drug therapy*
  • Plaque, Atherosclerotic / metabolism
  • Rabbits
  • Random Allocation
  • Simvastatin / pharmacology*
  • Thromboplastin / metabolism
  • Up-Regulation


  • 2-(2-chloro-4-fluorobenzyl)-3-(4-fluorophenyl)-7-(trifluoromethyl)-2H-indazole
  • Anticholesteremic Agents
  • Chemokine CCL2
  • Drug Combinations
  • Indazoles
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Thromboplastin
  • Simvastatin
  • Cyclooxygenase 2