Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6C ^high monocytosis: Evidence that the effects are not apolipoprotein e dependent

Bacground-: 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 objective was to determine whether the atheroprotective effects of LRP1 require interaction with apoE, one of its ligands with multiple beneficial effects. Methods and Result-: 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 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. Conclusion-: Low-density lipoprotein receptor protein 1 exerts antiatherogenic effects via pathways independent of apoE^-/- involving macrophage apoptosis and monocyte recruitment.