An agonist of liver X receptor slows valvular disease in a hypercholesterolemia mouse model.

ABSTRACT

BACKGROUND AND AIM OF THE STUDY Cholesterol is a known risk factor in aortic stenosis and valve degeneration, and the liver X receptor (LXR) is a regulator of cholesterol and phospholipid metabolism. It was hypothesized that an LXR agonist would reduce calcium and lipid deposition in aortic valves. METHODS: Apolipoprotein E-/- (ApoE-/-) mice fed a high-fat diet were implanted with glutaraldehyde-fixed porcine valve fragments. The animals were treated with either the LXR agonist T1317 or vehicle for eight weeks. RESULTS: The LXR agonist reduced lipid deposition in native aortic roots and sinuses about two-fold (p < 0.05), and echocardiography revealed lower transvalvular velocities in vivo (p < 0.05). Similarly, treatment with the LXR agonist significantly reduced the calcium content (by ca. 50%, p < 0.05) and lipid content (by ca. 20%, p < 0.01) of explanted porcine valve tissue. Serum low-density lipoprotein (LDL) and total cholesterol levels were also lower in treated mice (p < 0.01). Serum levels of the inflammatory chemokine platelet factor 4 were reduced by 30% compared to controls. Cultured valvular cells treated with oxidized LDL (ox-LDL) developed greater numbers of calcific nodules. The ox-LDL treatment of valvular endothelial cells increased adhesion to mononuclear cells, while the LXR agonist reversed both the increase in adhesion and vascular cell adhesion protein-1 expression mediated by ox-LDL. CONCLUSION: The data acquired suggested that calcium and lipid deposition in heart valves can be altered by inhibiting lipid metabolism via LXR, and that the mechanism may involve inflammatory cell signaling. These results indicate that enhancement of cholesterol efflux activity may have the potential to reduce bioprosthetic and native valve degeneration.