Low-Density Lipoprotein Receptor–Related Protein 1 Prevents Early Atherosclerosis by Limiting Lesional Apoptosis and Inflammatory Ly-6Chigh Monocytosis
Evidence That the Effects Are Not Apolipoprotein E Dependent
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 objective was to determine whether the atheroprotective effects of LRP1 require interaction with apoE, one of its ligands with multiple beneficial effects.
Methods and 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-Chigh monocytes. Finally, there were 3.6- and 2.4-fold increases in Ly6-Chigh 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.
- apolipoproteins E
- low-density lipoprotein receptor–related protein 1
- Ly6-C antigen, mouse
- Received March 13, 2011.
- Accepted May 25, 2011.
- © 2011 American Heart Association, Inc.