Low-Density Lipoprotein Receptor–Related Protein 1 Prevents Early Atherosclerosis by Limiting Lesional Apoptosis and Inflammatory Ly-6C Monocytosis Evidence That the Effects Are Not Apolipoprotein E Dependent

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 / M LRP1 / 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 / M LRP1 / versus apoE / mice. Lesion necrosis was also increased (6 fold) in apoE / M LRP1 / versus apoE / mice. Compared with apoE / mice, the spleens of apoE / M LRP1 / mice contained 1.6and 2.4-fold more total and Ly6-C monocytes. Finally, there were 3.6and 2.4-fold increases in Ly6-C and CC-chemokine receptor 2–positive cells in lesions of apoE / M LRP1 / versus apoE / mice, suggesting that accumulation of apoptotic cells enhances lesion