Accelerated atherosclerosis in C57B1/6 mice transplanted with ApoE-deficient bone marrow

Apolipoprotein E (apoE), a high affinity ligand for lipoprotein receptors, is synthesized by the liver and extrahepatic tissues, including cells of th e monocyte/macrophage cell lineage. The role of monocyte/macrophage-derived apoE in atherogenesis was assessed by transplantation of apoE-deficient (a poE -/-) bone marrow into normolipidemic C57B1/6 mice. No significant effec t could be demonstrated on serum apoE levels in C57B1/6 mice, transplanted with apoE-deficient bone marrow compared with control transplanted mice. Fu rthermore, no consistent effect on serum cholesteryl esters and triglycerid e concentrations could be demonstrated on either a standard chow diet or a high cholesterol diet. Quantitative analysis of atherosclerosis in mice tra nsplanted with apoE-deficient bone marrow, after two months on a high chole sterol diet, revealed a 4-fold increase in the atherosclerotic lesion area as compared to animals transplanted with apoE +/+ bone marrow. Analysis of the ability of apoE-deficient macrophages to release cholesterol after load ing with acetylated LDL revealed that the release of cholesterol from apoE- deficient macrophages was impaired as compared to wild-type macrophages in the absence and the presence of specific cholesterol accepters. In conclusi on, apoE production by macrophages retards the formation of atherosclerotic plaques, possibly by mediating cholesterol efflux. We anticipate that phar macological approaches to increase apoE synthesis and/or secretion by macro phages might be beneficial for the treatment of atherosclerosis. (C) 2000 E lsevier Science Ireland Ltd. All rights reserved.