Inhibition of cytosolic phospholipase A2 suppresses production of cholesteryl ester through the reesterification of free cholesterol but not formation of foam cells in oxidized LDL-stimulated macrophages

Abstract

Macrophage-derived foam cells are formed as a result of the accumulation of cholesteryl ester (CE) not only in cytoplasm where CE is produced by the reesterification of free cholesterol derived from oxidized low density lipoprotein (OxLDL) undergoing hydrolysis, but also in lysosomes where the remaining CE of OxLDL is deposited. We examined the possible involvement of cytosolic phospholipase A2s (cPLA2s) in the production of CE through the reesterification and in the formation of foam cells. In [ 3H]oleic acid-labeled human acute monocytic leukemia (THP-1) cell-derived macrophages (THP-M) and mouse peritoneal macrophages (MPM), which possessed at least cPLA3α and cPLA2γ, stimulation with OxLDL induced the production of [3H]cholesteryl oleate ([3H]CE). The production was suppressed by an inhibitor of cPLA2s. However, the inhibitor tended to slightly decrease total intracellular levels of CE, and did not affect the formation of foam cells, as estimated by staining with Oil Red O. In cPLA2α-knockout MPM, OxLDL-induced increases in [3H]CE and total CE did not differ from those in wild-type MPM. Our results suggest that cPLA2s other than cPLA2α contribute to the supply of fatty acids, which are utilized for the production of CE through the reesterification, in OxLDL-stimulated macrophages. However, the formation of foam cells could not be inhibited only by the suppression of cPLA2-mediated CE production. © 2008 Pharmaceutical Society of Japan.