Role of leukocyte-specific LDL receptors on plasma lipoprotein cholesterol and atherosclerosis in mice

Bone marrow-derived macrophages and lymphocytes express LDL receptors (LDL-R), which allow these cells to take up cholesterol-rich lipoproteins. Although these cells are ubiquitously distributed in the body, it is not known whether they influence plasma cholesterol. Macrophages and T lymphocytes also are found in atherosclerotic lesions, but it is not known whether their LDL-R expression plays a role in atherosclerosis. To address these questions, we subjected LDL-R -/- mice to total body irradiation to eliminate their endogenous bone marrow-derived cells and repopulated them with either LDL-R-expressing wild-type bone marrow (treated mice) or LDL-R -/- bone marrow (control mice). Thus, the only difference between the two groups of mice was the ability of the bone marrow-derived cells to express the LDL-R in the treated mice. Plasma cholesterol levels were similar in the two groups of mice at 8 and 16 weeks after transplantation. Chromatographic separation of the lipoproteins revealed similar lipoprotein cholesterol distributions. Although the extent of lesion area in the aortic valves of the high-fat-diet-fed mice was more severe than that in the chow-fed mice, lesions appeared similar between control and treated mice given either chow or high-fat diet. Abundant LDL-R expression was detected in the lesions of treated mice, whereas the lesions of control mice showed no LDL-R expression, indicating that donor-derived leukocytes had migrated into the lesions of the recipient mice. Thus, bone marrow transplantation can be used as a tool to replace the endogenous bone marrow-derived cells in the artery wall with those of the donor origin.