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


CONCLUSIONS
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.
Division of Cardiothoracic Surgery, Department of Surgery, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Davis Building Room 6014, Los Angeles, California 90048, USA. Haimei.Wang@hsc.utah.edu
Haimei
H
Wang
Sorel
S
Goland
Kevin
K
Burton
Lawrence S C
LS
Czer
Ernst R
ER
Schwarz
Alfredo
A
Trento
D000818:Animals; D001021:Aortic Valve / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006349:Heart Valve Diseases / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D006350:Heart Valve Prosthesis; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000150:complications*; D050356:Lipid Metabolism / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000494:pharmacology; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D001057:Apolipoproteins E; D002118:Calcium; D006845:Hydrocarbons, Fluorinated; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C099252:oxidized low density lipoprotein