Background
We previously demonstrated that macrophage low-density lipoprotein receptor (LDLR)-related protein 1 (LRP1) deficiency increases atherosclerosis despite antiatherogenic changes including decreased uptake of remnants and increased secretion of apolipoprotein E (apoE). Thus, our
Conclusion
Low-density lipoprotein receptor protein 1 exerts antiatherogenic effects via pathways independent of apoE involving macrophage apoptosis and monocyte recruitment.
Results
We examined atherosclerosis development in mice with specific deletion of macrophage LRP1 (apoE(-/-) MΦLRP1(-/-)) and in LDLR(-/-) mice reconstituted with apoE(-/-) MΦLRP1(-/-) bone marrow. The combined absence of apoE and LRP1 promoted atherogenesis more than did macrophage apoE deletion alone in both apoE-producing LDLR(-/-) mice (+88%) and apoE(-/-) mice (+163%). The lesions of both mouse models with apoE(-/-) LRP1(-/-) macrophages had increased macrophage content. In vitro, apoE and LRP1 additively inhibit macrophage apoptosis. Furthermore, there was excessive accumulation of apoptotic cells in lesions of both LDLR(-/-) mice (+110%) and apoE(-/-) MΦLRP1(-/-) mice (+252%). The apoptotic cell accumulation was partially due to decreased efferocytosis as the ratio of free to cell-associated apoptotic nuclei was 3.5-fold higher in lesions of apoE(-/-) MΦLRP1(-/-) versus apoE(-/-) mice. Lesion necrosis was also increased (6 fold) in apoE(-/-) MΦLRP1(-/-) versus apoE(-/-) mice. Compared with apoE(-/-) mice, the spleens of apoE(-/-) MΦLRP1(-/-) mice contained 1.6- and 2.4-fold more total and Ly6-C(high) monocytes. Finally, there were 3.6- and 2.4-fold increases in Ly6-C(high) and CC-chemokine receptor 2-positive cells in lesions of apoE(-/-) MΦLRP1(-/-) versus apoE(-/-) mice, suggesting that accumulation of apoptotic cells enhances lesion development and macrophage content by promoting the recruitment of inflammatory monocytes.