Gordon A. Francis, Canada
University of British Columbia MedicinePresenter of 1 Presentation
Defective lysosomal cholesteryl ester processing promotes the formation and altered phenotype of arterial smooth muscle but not macrophage foam cells in humans and mice
Abstract
Background and Aims
We previously reported that smooth muscle cells (SMCs) comprise the majority of foam cells in human and apoE-/- mouse atheromas. In the present study we investigated the potential role of lysosomal dysfunction and lysosomal acid lipase (LAL) in foam cell formation by SMCs and macrophages in vitro and in vivo.
Methods
Human and mouse arterial SMCs and macrophages treated with aggregated LDL (agLDL) to generate foam cells, and foam cells isolated from apoE-deficient mice, were investigated for lysosomal cholesterol metabolism and sites of lipid storage. Cultured foam cells and human and mouse atheromas were analyzed for LAL expression.
Results
Following agLDL loading, confocal microscopy revealed retention of cholesteryl ester droplets within lysosomal compartments in human and mouse SMCs, while macrophages showed most lipid droplets in cytosolic compartments. Macrophage foam cells isolated from apoE-/- mice showed higher cell granularity as determined by forward scatter on fluorescence-activated cell sorting when compared to SMC foam cells. SMC foam cells showed no defects in lysosomal acidification or proteolysis, however, LAL expression and activity was markedly reduced in SMCs compared to macrophages both in culture and in human and mouse atheromas.
Conclusions
Arterial SMC foam cells show a striking reduction in LAL activity and storage of lipoprotein cholesteryl esters primarily in lysosomal compartments when compared to macrophage foam cells both in vitro and in vivo. This provides a likely reason for the propensity of SMCs to form the majority of atheroma foam cells, and a novel target for the prevention and regression of atherosclerosis.