Cell type-specific contribution of low-density lipoprotein receptor to atherosclerosis

Area of Science:

• Cardiovascular Biology
• Immunology
• Metabolic Diseases

Background:

• Elevated low-density lipoprotein (LDL) is a primary risk factor for cardiovascular disease (CVD).
• Upregulating the LDL receptor (LDLR) is a therapeutic strategy to lower LDL and prevent/treat CVD.
• The specific role of LDLR in various aortic cell types during atherosclerosis remains incompletely understood.

Purpose of the Study:

• To investigate the contribution of LDLR in distinct aortic cell populations to the development of atherosclerosis.
• To determine the impact of cell-specific LDLR deficiency on diet-induced hypercholesterolemia and atherosclerotic plaque formation in mice.

Main Methods:

• Mice with hepatocyte-specific LDLR deletion were fed a high-fat, high-cholesterol diet to induce hypercholesterolemia and atherosclerosis.
• Subsequent deletion of LDLR in endothelial cells, smooth muscle cells, or myeloid cells was performed.
• Atherosclerotic plaque burden, immune cell infiltration in the aorta, and foam cell formation in vitro were analyzed.

Main Results:

• Hepatocyte-specific LDLR deletion induced hypercholesterolemia and atherosclerosis.
• Further LDLR deletion in endothelial or smooth muscle cells did not significantly alter atherosclerosis.
• Myeloid-selective LDLR ablation markedly reduced atherosclerotic plaque formation and decreased T cell and NKT cell percentages in the aorta.

Conclusions:

• LDLR plays a critical role in myeloid cells in the progression of atherosclerosis.
• Targeting LDLR in a cell-specific manner, particularly in myeloid cells, may offer a more effective therapeutic strategy for cardiovascular disease prevention and treatment.