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.

Abstract

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.

• Authors: Chiara Giannarelli, Giovanni Cimmino, Thomas M Connolly, Borja Ibanez, Josè M Garcia Ruiz, Matilde Alique, M Urooj Zafar, Valentin Fuster, Giora Feuerstein, Juan J Badimon
• Journal: European heart journal (Eur Heart J) Vol. 33 Issue 2 Pg. 264-73 (Jan 2012) ISSN: 1522-9645 [Electronic] England
• PMID: 21606082 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Anticholesteremic Agents (pharmacology)
• Aorta, Abdominal
• Aortic Diseases (drug therapy, metabolism)
• Atherosclerosis (drug therapy, 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, drug effects)
• Plaque, Atherosclerotic (drug therapy, metabolism)
• Rabbits
• Random Allocation
• Simvastatin (pharmacology)
• Thromboplastin (metabolism)
• Up-Regulation