Model systems in cell culture for the study of atherogenesis

Abstract

Tissue culture proved to be convenient for the development of simple model systems in which it was possible to study some aspects of human atherosclerosis. Thus it became apparent indeed that inhibition of lysosomal cholesterol ester hydrolase with chloroquine combined with exposure of the cultured cells to LDL can reproduce lesions resembling an atheroma. Pretreatment of the cells with sodium ascorbate afforded some protection for the lysosomal enzymes against the action of chloroquine. It appears that the lysosomal hydrolases show no preference for the degradation of cholesterol linoleate. Thus the known accumulation of cholesterol oleate in atheroma is most probably due to preferential use of oleic acid for cholesterol esterification in the cells and in the atheroma. Once the inhibition of the cholesterol esterase is removed (in the model system by withdrawal of chloroquine) cholesterol ester hydrolysis ensues and in the presence of suitable acceptors it is possible to remove the accumulated cholesterol from the cells into the medium. The acceptors used were complexes of phospholipids and apoproteins derived from high density lipoprotein of serum. Cholesterol removal from both normal and cholesterol enriched cells was achieved also in the presence of serum which had been freed from VLDL and LDL. Under such experimental conditions the rate of cholesterol removal was related to the concentration of the VLDL and LDL free serum, but the activity of LCAT was not necessary for cholesterol removal. These results indicate that perhaps also in vivo some aspects of atherosclerosis might be reversible and that apolipoprotein of high density lipoproteins could play a role in the clearance of cholesterol from cells in peripheral tissue.