Low density lipoprotein receptor of macrophages facilitates atherosclerotic lesion formation in C57B1/6 mice

Macrophage-derived foam cells play an important role in the initiation and progression of atherosclerosis, To examine the role of the macrophage low d ensity lipoprotein receptor (LDLr) in atherosclerotic lesion formation, bon e marrow from LDLr knockout [LDLr(-/-)] mice was transplanted into irradiat ed wild-type C57B1/6 [LDLr(+/+)] mice. After 3 months on an atherogenic die t, C57B1/6 mice, reconstituted with LDLr(-/-) bone marrow, showed a mean le sion area of 34.7X10(3)+/-22.4x10(3) mu m(2) compared with 100.8X10(3)+/-33 .0X10(3) mu m(2) (P<0.001) in control C57B1/6 mice that were transplanted w ith LDLr(+/+) bone marrow. There were no significant differences in total s erum cholesterol, triglyceride levels, and lipoprotein profiles between the 2 groups. Histochemical analysis of macrophage LDLr expression in the athe rosclerotic lesions indicated that C57B1/6 mice, reconstituted with LDLr(+/ +) bone marrow, showed extensive staining of the foam cells in the atherosc lerotic lesions, whereas mice reconstituted with LDLr(-/-) bone marrow show ed only a few LDLr-positive foam cells. In vitro, peritoneal macrophages is olated from wild-type C57B1/6 mice were, respectively, 4.7- and 10.7-fold m ore effective in cell association and degradation of atherogenic I-125-beta -very low density lipoprotein than were LDLr(-/-) peritoneal macrophages, e stablishing that the LDLr on macrophages is important for the interaction o f macrophages with P-very low density lipoprotein. It is concluded that the LDLr on macrophages can facilitate the development of atherosclerosis, pos sibly by mediating the uptake of atherogenic lipoproteins.