Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering

Area of Science:

• Cardiovascular Research
• Immunology
• Metabolic Diseases

Background:

• Statins are known to induce atherosclerotic plaque regression in humans, evidenced by decreased macrophage content.
• The precise mechanisms driving this regression, particularly the role of macrophages, remain incompletely understood.

Purpose of the Study:

• To elucidate the mechanisms by which statins and cholesterol lowering induce macrophage reduction in atherosclerotic plaques.
• To investigate the contribution of monocyte infiltration, macrophage egress, and local proliferation to plaque regression.

Main Methods:

• Utilized the APOE*3-Leiden.CETP mouse model with humanized lipoprotein metabolism.
• Employed cell fate mapping, fluorescent bead labeling, and mass spectrometry to assess monocyte/macrophage dynamics and drug accumulation.
• Correlated serum LDL-cholesterol and plaque lipid levels with in situ macrophage proliferation rates.

Main Results:

• Systemic cholesterol lowering via atorvastatin or dietary restriction inhibited monocyte infiltration and reversed macrophage accumulation.
• Reduced monocyte influx, enhanced macrophage egress, and atorvastatin accumulation did not sufficiently explain the observed decrease in plaque macrophages.
• Suppression of local macrophage proliferation was identified as the dominant mechanism driving plaque regression.

Conclusions:

• Macrophage proliferation, rather than altered influx or egress, is the primary determinant of macrophage turnover in atherosclerotic plaques undergoing regression.
• Targeting local macrophage proliferation represents a promising therapeutic strategy for inducing atherosclerotic plaque regression.