Related Experiment Video
Updated: Jun 7, 2026
A Murine Model of Hyperlipidemia-Induced Heart Failure with Preserved Ejection Fraction
Published on: March 29, 2024
An agonist of liver X receptor slows valvular disease in a hypercholesterolemia mouse model
Haimei Wang1, Sorel Goland, Kevin Burton
1Division 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
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.
Insights
Activating the liver X receptor (LXR) with an agonist reduced calcium and lipid buildup in heart valves. This suggests LXR agonists may help prevent valve degeneration by modulating cholesterol metabolism and inflammation.
Area of Science:
- Cardiovascular Research
- Metabolic Disease
- Pharmacology
Background:
- Cholesterol accumulation is a key factor in aortic stenosis and heart valve degeneration.
- Liver X receptor (LXR) plays a crucial role in regulating cholesterol and phospholipid metabolism.
Purpose of the Study:
- To investigate the potential of an LXR agonist to mitigate calcium and lipid deposition in aortic valves.
- To explore the impact of LXR activation on cholesterol metabolism and inflammatory pathways in valve degeneration.
Main Methods:
- Apolipoprotein E-deficient (ApoE-/-) mice on a high-fat diet received porcine valve implants.
- Animals were treated with an LXR agonist (T1317) or vehicle for eight weeks.
- Analysis included lipid and calcium content in native and explanted valves, echocardiography, and serum marker assessment.
Main Results:
- LXR agonist treatment significantly reduced lipid deposition in aortic roots and sinuses.
- Echocardiography showed lower transvalvular velocities in treated mice.
- Calcium and lipid content in explanted porcine valves were reduced, along with lower LDL and total cholesterol levels.
- Oxidized LDL-induced calcification and inflammatory cell adhesion in valvular cells were reversed by the LXR agonist.
Conclusions:
- Inhibiting lipid metabolism via LXR activation can alter calcium and lipid deposition in heart valves.
- The mechanism likely involves modulation of inflammatory cell signaling pathways.
- Enhancing cholesterol efflux through LXR activation may offer a therapeutic strategy for native and bioprosthetic valve degeneration.
