Phenotypic high-throughput screening in atherosclerosis research: focus on macrophages

Area of Science:

• Cardiovascular Science
• Cell Biology
• Pharmacology

Background:

• Atherosclerosis involves arterial lesions with diverse cell types, including macrophage foam cells.
• Lesion rupture can lead to thrombosis and tissue infarction.
• Macrophage foam cells accumulate cholesterol from modified lipoproteins, like oxidized low-density lipoprotein (LDL).

Purpose of the Study:

• To address the lack of therapies targeting atherosclerotic lesion cellular composition.
• To identify compounds that modulate macrophage cholesterol metabolism within arterial lesions.

Main Methods:

• Phenotypic high-throughput drug screening.
• Assays to identify compounds reducing oxidized LDL uptake by macrophages.
• Assays to identify compounds increasing cholesterol efflux from macrophages.

Main Results:

• Drug screens have been developed to identify compounds impacting macrophage cholesterol handling.
• Potential for screens targeting macrophage apoptosis and efferocytosis in active lesions.

Conclusions:

• Current atherosclerosis treatments primarily focus on lipid levels, not lesion cellular makeup.
• Novel drug discovery strategies are needed to target cellular processes within atherosclerotic plaques.
• Phenotypic screening offers a promising approach to develop new atheroprotective therapies.