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

• Published in: European heart journal Vol. 33; no. 2; pp. 264 - 273
• Main Authors: Giannarelli, Chiara, Cimmino, Giovanni, Connolly, Thomas M., Ibanez, Borja, Garcia Ruiz, Josè M., Alique, Matilde, Zafar, M. Urooj, Fuster, Valentin, Feuerstein, Giora, Badimon, Juan J.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.2012
• Subjects: Animals; Anticholesteremic Agents - pharmacology; Aorta, Abdominal; Aortic Diseases - drug therapy; Aortic Diseases - metabolism; Atherosclerosis (general aspects, experimental research); Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Chemokine CCL2 - metabolism; Cyclooxygenase 2 - metabolism; Disease Progression; Drug Combinations; Drug Synergism; Indazoles - pharmacology; Liver X Receptors; Magnetic Resonance Angiography; Medical sciences; 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; Inflammation; MRI imaging; Nuclear receptor LXR; Experimental models; Atherosclerosis; Nuclear receptor; Stabilization; Liver; Simvastatin; Regression; Cardiovascular disease; Activation; Nuclear magnetic resonance imaging; Vascular disease; Medical imagery; Models; Circulatory system; Cardiology; Biological receptor
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehr136

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.